Kathleen Brady - US grants

There have been promising advances in the use of pharmacologic agents for the treatment of cocaine dependence. While it is apparent that medications may be useful in the treatment of cocaine dependence, most studies indicate that medications work in some, but not all, cocaine abusers. With the variety of pharmacologic agents currently under investigation and the known heterogeneity of the cocaine-abusing population, a mechanism for sub-typing cocaine abusers for the purpose of matching to the most appropriate pharmacologic treatment would be of value. As many cocaine abusers are reported to have mood disorders, one logical way to subtype patients is on the presence or absence of a mood disorder. The specific aims of the current proposal are: 1) to use state-of-the-art psychiatric instruments to diagnose co-existing psychiatric disorders and monitor psychiatric symptoms in patients presenting for cocaine treatment, and 2) to conduct a 12-week, placebo-controlled trial comparing the efficacy of carbamazepine in the treatment of cocaine-dependence in patients with and without affective disorders. More specifically, the protocol proposes a double-blind, placebo-controlled clinical trial of carbamazepine in patients with and without affective disorders over a 12-week treatment period with a 24-week follow-up assessment. The unique features of the protocol are that: 1) it will provide placebo-controlled data concerning the efficacy of carbamazepine and the serum level/clinical efficacy of carbamazepine in the treatment of cocaine dependence; 2) it is designed to stratify subjects with lifetime history of affective illness between the carbamazepine and placebo groups so a potential differential effect of medications on these two groups can be investigated; 3) all patients will be drug free at the time of initiation of drug treatment; 4) it includes a riboflavin marker in the both placebo and drug groups to permit evaluation of patient compliance; and 5) it uses state-of-the-art assessment instruments to evaluate the treatment impact on, not only cocaine use and craving, but outcome variables related to several additional dimensions. As the cocaine abuse problem in this country has grown to such large proportions, it is becoming increasingly important to develop more efficient and cost effective methods of substance abuse treatment. Matching patients to treatment on the basis of psychiatric co-morbidity is one promising avenue for designing treatments for specific populations.

DESCRIPTION: (Applicant's Abstract) The high prevalence of victimization and its sequelae among cocaine-dependent individuals is an issue of much current concern. Recent studies have suggested meaningful relationships between substance use disorders, victimization and psychiatric disorders most notably Post-traumatic Stress Disorder (PTSD). While it has been estimated that as many as 30% of individuals with substance use disorders suffer from PTSD, the appropriate treatment of these individuals remains to be elucidated. The proposed project is a Stage I project designed to develop and pilot test a treatment manual which specifically targets cocaine-dependent individuals who have current crime-related PTSD (CR-PTSD). The manual will be an integration of a cognitive behavioral therapy manual which has been developed for the treatment of PTSD with a cognitive behavioral therapy manual which has been developed for the treatment of cocaine dependence. A unique feature of the manual developed will be the addition of specific training in HIV-risk reduction strategies. The three year project is divided into 4 phases: manual development and the development of specific integrity, competence and adherence measures for the manuals; therapist training and pilot therapy (10 subjects) deliveries; manual revision; and pilot testing of the manual in 25 subjects. Process evaluation will guide the refinement of the manual during the course of the project. Treatment outcome will be evaluated along multiple dimensions. The specific aims of this proposal are: 1) To develop and refine a treatment manual for CBT targeting issues specific to cocaine-dependent individuals with CR-PTSD which also addresses HIV-risk behaviors. 2) To develop measures of therapist competence, adherence and integrity specific to the integrated treatment manual. 3) To develop and imp1ement a training program for therapists to use the integrated treatment manual. 4) To pilot test the manual in 25 individuals with concurrent CR-PTSD and cocaine-dependence. In summary, this project targets the treatment of cocaine-dependent individuals who have been victims of violence and have current CR-PTSD. If the data gathered in this project is promising, a proposal to support the implementation of the manual developed in a larger, Stage II, controlled clinical trial will be developed. All participants will be assessed initially and at 6 and 12 months by two structured interviews, the Individual Assessment Profile (IAP) and the Risk for AIDS Behaviors Questionnaire (RAB). Outcome measures of interest for each six month period are: number of positive urinalysis, self reported drug use days, days in treatment, number of people with whom drug injection equipment was shared, number of arrests, days employed or in school. To study intensively immediate precipitants of first events of drug use fol-lowing a period of abstinence. Such study is to include the context of background, person, treatment, and environmental determinants of lapses. To evaluate the adequacy of the proposed model in explaining lapses and empir-ical definitions of relapse. The breadth of these analyses will also reflect on and sharpen existing theories of relapse. The methodology for pursuing these goals entails a multivariate correlational design that incorporates an initial classification of clients according to gender. A detailed assessment of clients will occur at treatment entry. Subjects and their collaterals will be interviewed at months 1 through 6, 9., and 12 after treatment entry to collect detailed information on their substance use and on lapses/relapses that have occurred since their last assessment. Taken together, this research will provide important information needed to expand knowledge regarding the myriad of factors and processes associated with lapse/relapse and their interplay.

APPLICANT'S ABSTRACT: The goal of this health services research application is to improve the outcome of services for persons with alcohol-related problems. Proposed to achieve this goal, is the introduction of an additional brief intervention aimed at reducing problem drinking and its medical and social consequences, to the usual armamentarium of alcohol-related treatments. The experimental treatment (naltrexone) has demonstrated efficacy in controlled clinical trials in academic settings, but has not been previously tested in a naturalistic setting. Potentially, the research initiative proposed presents an opportunity to significantly improve the effectiveness of services delivered in community-based settings. The experimental paradigm is a randomized clinical trial with three comparison service conditions (usual services; usual services plus adjunctive naltrexone; usual services plus placebo). The addition of the placebo group allows for an evaluation of the nonspecific effects of medical monitoring. The exclusion factors for participation have been limited to ensure the generalizability of the study and, therefore, assess the effectiveness of naltrexone in a real practice setting. Principal hypotheses tested involve sustained improvements in alcohol-related outcomes such as reductions in alcohol use and use of medical, legal, law enforcement and other services for persons in the experimental condition. Measures of functioning (family, social, psychological) and alcohol use (quantity, frequency) are assessed at baseline and prospectively for twelve months. Clinical and other service (medical, legal, etc.) utilization and their costs are monitored continuously. The setting for the study will be a county-level, private/non-profit alcohol and substance abuse agency, in a mostly rural southeastern state which has approximately 25-35% representation of African Americans in the population. The application is responsive to Healthy People 2000's priority area of alcohol abuse reduction and alcoholism treatment; RFA 97-001's objective of identifying and assessing the effectiveness and outcomes of alcohol-related treatment and prevention services; and is offered as a public-academic services research collaboration.

Recent studies have suggested meaningful relationships between alcohol abuse and dependence, victimization and post-traumatic stress disorder (PTSD). It has been suggested that as many as 30% of alcoholic individuals have been the victims of childhood or adult physical or sexual assault. While PTSD can result from a variety of traumatic events, crime-related events, including childhood sexual and physical assault, are a common cause of PTSD (CR-PTSD) and will be the focus of this proposal. It is likely that untreated CR-PTSD can worsen the course of alcohol use disorders and make it difficult to decrease consumption and attain abstinence. The goal of the proposed study is to investigate the use of a medication, sertraline, which has been shown in preliminary studies to decrease alcohol consumption and to decrease the symptoms of CR-PTSD, in individuals with concurrent CR-PTSD and an alcohol use disorder. The study will be a 12 week placebo-controlled double-blind study with a 1 week placebo wash-out. All subjects will receive 12 sessions of concurrent cognitive behavioral therapy for alcoholism. Subjects will include 122 individuals who meet DSM-IV criteria for alcohol abuse or dependence and current CR-PTSD. Comprehensive evaluation will be done at study entry, treatment termination, 6,9, and 12 months after study entry. Outcome will be evaluated along multiple dimensions. The specific aims of this proposal are the following: (1) To use state-of-the-art psychological and psychiatric instruments to determine histories of trauma, sequelae of trauma and psychiatric symptoms among individuals presenting for alcohol treatment. (2) To conduct a 12-week double-blind placebo-controlled outpatients clinical trial of sertraline in individuals with concurrent alcoholism and CR-PTSD. (3) To evaluate the efficacy of the experimental treatment over the course of one year as measured by changes in substance use, CR-PTSD symptoms and psychiatric symptoms as well as psychosocial indicators. In summary, this project targets the treatment of individuals with alcohol use disorders who have been victims of violence and have current CR-PTSD. The efficacy of a pharmacologic treatment targeting both decreased alcohol consumption and decreased CR-PTSD symptomatology will be explored. The overall goal of the project is to further explore the relationship between CR-PTSD and alcoholism and to improve treatment outcome for this population.

A placebo controlled, double blind trial of sertraline; hypothesis is subjects in drug treated group will improve in symptoms of PTSD and have decreased alcohol consumption.

DESCRIPTION (provided by applicant): This is a competing renewal for a mid-career investigator award application to support the efforts of Dr. Kathleen T. Brady, M.D., Ph.D. in conducting and mentoring patient-oriented drug abuse research. Dr. Brady has been continuously federally funded to conduct patient-oriented research with substance abusing individuals since completing her psychiatric residency training in 1989. Her particular areas of interest are in psychiatric comorbidity with substance use disorders and the pharmacotherapy of substance use disorders. In the period that has been supported by the initial application (1999-present), Dr. Brady has submitted a successful application to become a center in the NIDA Clinical Trials Network, and a successful center application to begin a specialized center for translational work on sex and gender factors affecting substance use disorders. She is also the site PI on a study of the genetics of cocaine dependence, and the PI for a core research component of two different MUSC research Centers (Alcohol Research Center and the Women's Research Center). These projects are focused on stress reactivity and relapse. In addition, during this funding period, she has served as a co-investigator for a number of studies involving pharmacotherapeutic interventions in individuals with substance use and co-morbid psychiatric disorders. Dr. Brady has a strong track record in mentoring in clinical research. In the period supported by the initial application, she has served as a primary or secondary mentor to five K-awardees and four post-doctoral fellows. She is currently the Director of the Addiction Psychiatry Fellowship Program and the Co-Director of a NIDA-funded post-doctoral research training program. She has recently been appointed as the Associate Director of the MUSC GCRC. The focus of her GCRC work will be to improve training opportunities and activities. Her long-term career goals are to continue work in patient-oriented substance abuse research in new directions that build on existing studies. During the period to be covered by this renewal, Dr. Brady plans to expand her exploration of the stress-relapse connections. She will continue to collaborate with basic science researchers in translational projects as well as initiate studies of pharmacotherapeutic and psychotherapeutic interventions designed to improve stress resilience in substance-dependent individuals. The candidate would also use the time and funding provided through this award to continue to expand her activities in mentoring fellows and junior faculty.

There is a disconnect between research concerning effective treatments for substance use disorders and drug abuse treatment in community based settings. The NIDA Clinical Trial Network (CTN) proposes to bridge this gap by the partnering of academic medical centers and community treatment programs in designing and implementing clinical trials and health services research in sites spread throughout the United States. This application describes the structure, function and individuals involved in a proposed Southeastern NODE of the CTN. In the Southeastern NODE, we have assembled an experienced group of investigators with a variety of research experiences. This group has conducted single and multi-site trials in collaboration with members of the existing CTN. The participating community treatment programs are experienced, well-established programs serving diverse patient populations. Many of these programs have already worked with the researchers involved, and all are enthusiastic about the opportunities offered by the CTN. The specific aims of this proposal are: (1) To develop an infrastructure to allow for the conduct of substance abuse research trials in the Southeastern region of the United States through a partnership with the Medical University of South Carolina and a network of community treatment programs. (2) To work collaboratively with NIDA and the other NODEs in the CTN in: a) directing at least one research trial per year investigating medications, psychosocial treatment, health services or practice research in the drug abuse area; b) participating in at least two additional research studies per year. (3) To work collaboratively with NIDA and the other CTN NODEs through the Network Steering Committee to develop and maintain the framework for the CTN including the development of operating policies and procedures, and the formation and participation in subcommittees. The CTN provides a unique and exciting opportunity to work collaboratively with colleagues from the Southeast and throughout the nation in exploring effective treatments for substance use disorders.

varicella zoster virus; shingles; viral vaccines; human therapy evaluation; HIV infections; active immunization; live vaccine; AIDS therapy; clinical research; human subject;

DESCRIPTION (adapted from the application s abstract): This award will prepare Kathleen A. Brady, M.D., for a career as an independent investigator in HIV epidemiology with a special emphasis on the prevention and treatment of long term complications of HIV infection. She proposes a comprehensive, interdisciplinary program that will provide her with the skills and experience necessary for independent clinical research. The training component includes advanced education in clinical epidemiology and dual mentorship from an internationally known infectious disease epidemiologist and a highly experienced HIV clinical researcher. The research component will focus on herpes zoster in the HIV-infected host. Herpes zoster has been a well recognized complication of HIV infection since the early stages of the HIV epidemic. With the introduction of protease inhibitors several years ago combination antiretroviral therapy has become routine and has improved the clinical course of HIV infection. However although many other opportunistic infections have significantly declined with these powerful new therapies, herpes zoster remains a problem for HIV-infected patients. The precise magnitude of this problem has not been determined. The proposed research will: (a) examine the impact of combination antiretroviral therapy on the incidence of herpes zoster in HIV-infected adults; (b) establish the risk factors for herpes zoster in these same patients; and (c) utilize this information to design a safety and immunogenicity trial of live-attenuated varicella vaccine in patients infected with HIV.

There has been much recent interest in the relationship between stress, alcohol use disorders and relapse to alcohol use. Animal studies have consistently demonstrated a connection between a number of experimentally-induced stressors and both the initiation of alcohol use and reinstatement after a period of human laboratory procedures have been used to investigate the relationship between experimentally-induced stressors and craving, a likely precursor to relapse in real world situations. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, one of the main hormonal systems involved in the stress response, is seen with chronic alcohol consumption. This dysregulation may play a role in stress-reduced relapse. The endogenous opiate response system is also involved in the regulation of the HPA axis stress response and has been implicated in the pathophysiology of alcohol use disorders. Opiate antagonists, such as naltrexone, decrease alcohol craving and relapse in alcohol-dependent individuals and have effects on HPA axis function. Our research group is investigating the relationship between Post- traumatic Stress Disorder (PTSD) and alcohol use disorders. These disorders commonly co-occur and individuals with PTSD may use alcohol in an attempt to dampen traumatic memories and decrease painful symptoms of PTSD. Dysregulation of the HPA axis is a key pathophysiologic characteristic of PTSD. Our recent work indicates greater alcohol craving in alcoholism as compared to individuals with alcoholism only. In this component, the physiologic and subjective responsiveness (including alcohol craving) and response of the HPA axis to a stressful task will be explored in a group of individuals with alcohol dependence without PTSD, PTSD without alcohol dependence, and no PTSD or alcohol dependence. Following the initial stress task and procedure, subjects will be randomly assigned to receive 6 days of naltrexone or matching placebo and the stress task procedure will be repeated. In summary, this project is designed to build upon the ongoing research in the area of PTSD and alcohol use disorders by further exploration of the neurobiologic interface between alcoholism and PTSD. This study may provide valuable information about the role of the HPA axis and the opiate system in stress-induced relapse.

DESCRIPTION (provided by applicant): The common thread that ties all of the projects of the proposed SCOR together is relapse to drug abuse. MUSC has demonstrated a long-standing interest in substance abuse research as is clearly evidenced by strength in both basic science and clinical research in this area. Importantly, the proposed investigative team has experience in conducting translational research in an NIAAA-funded center initiative since 1996. While our track record in research and clinical efforts in substance abuse is strong, MUSC does not presently have the same strength in women's health initiatives. The SCOR would provide a catalyst to growth in this area. In developing the SCOR application, we gathered individuals with a unique blend of expertise from across campus. The interdisciplinary and cross-college nature of this initiative should ensure the sharing of ideas from multiple perspectives and guarantee that the SCOR has maximum impact on research and the general culture within MUSC. Specific Aims of the MUSC SCOR: Specific Aim #1: To set the occasion for focused, coordinated, integrated and unified efforts along a single program of gender-related research in substance use disorders at MUSC. Specific Aim #2: To build an infrastructure to encourage and support gender-based research growth throughout the campus. Specific Aim #3: To attract trainees and new faculty to the area of research, particularly patient-oriented research, in women's health issues. Specific Aim #4: To centralize various individual research efforts currently underway, as well as those proposed in the SCOR. Specific Aim #5: To produce a regional education and training resource for research in women's health. There are a total of five research components. All are focused on gender issues in relapse to substance use disorders. However, the varied investigations range from an exploration of sex differences in response to pharmacologic agents to investigations of gender differences in drug reinstatement in rodents, craving in humans and gender-specific treatment paradigms. Component #1: Sex Differences in an Animal Model of Relapse: Dr. Ronald See, an experienced pharmacologist, will be exploring gender differences in several well-developed animal models of drug self-administration reinstatement. Component #2: Gender Differences in Response to Cues in Cocaine Dependence: Dr. Kathleen Brady will lead this study of gender differences in response to cocaine-related cues and negative emotional states in men and women. This study will take place in the GCRC and involves the measurement of HPA axis response as well as autonomic and subjective response. Component #3: Gender, Menstrual Cycle and Smoking Cue Reactivity: Dr. Himanshu Upadhyaya will conduct a project studying the effect of menstrual cycle on the reactivity to nicotine and negative affect cues in humans. Component #4: Gender Influence on Preclinical Alcohol Pharmacology: Dr. Larry Middaugh will be using a rodent model to investigate the impact of gender and estrus state on the rewarding effects of ethanol and ethanol-conditioned stimuli. Component #5: Vocational Training for Drug-Dependent Women. Dr. Carrie Randall, the Co-PI of this project, will lead the research team of nurses and an experimental psychologist in this applied research project investigating gender-specific vocational services programs in unemployed recovering substance abusing women. This is an opportune time to develop a focused effort on research in women's health at MUSC. In terms of the thematic focus of the proposed SCOR, there is a convergence of opportunities and expertise in translational research in neuroscience and addiction. A cadre of talented and experienced basic scientists and clinical researchers from throughout MUSC interested in the SCOR has emerged and interdisciplinary collaboration and communication has been established. There is strong support from the leadership of MUSC. The focus on women's health and substance use disorders is sorely needed and complements many of the ongoing University efforts. Thus, the timing and thematic focus seem to ideally support the development of a Specialized Center of Research on Sex and Gender Factors Affecting Women's Health at MUSC.

DESCRIPTION (provided by applicant): The common thread that ties all of the projects of the proposed SCOR together is relapse to drug abuse. MUSC has demonstrated a long-standing interest in substance abuse research as is clearly evidenced by strength in both basic science and clinical research in this area. Importantly, the proposed investigative team has experience in conducting translational research in an NIAAA-funded center initiative since 1996. While our track record in research and clinical efforts in substance abuse is strong, MUSC does not presently have the same strength in women's health initiatives. The SCOR would provide a catalyst to growth in this area. In developing the SCOR application, we gathered individuals with a unique blend of expertise from across campus. The interdisciplinary and cross-college nature of this initiative should ensure the sharing of ideas from multiple perspectives and guarantee that the SCOR has maximum impact on research and the general culture within MUSC. Specific Aims of the MUSC SCOR: Specific Aim #1: To set the occasion for focused, coordinated, integrated and unified efforts along a single program of gender-related research in substance use disorders at MUSC. Specific Aim #2: To build an infrastructure to encourage and support gender-based research growth throughout the campus. Specific Aim #3: To attract trainees and new faculty to the area of research, particularly patient-oriented research, in women's health issues. Specific Aim #4: To centralize various individual research efforts currently underway, as well as those proposed in the SCOR. Specific Aim #5: To produce a regional education and training resource for research in women's health. There are a total of five research components. All are focused on gender issues in relapse to substance use disorders. However, the varied investigations range from an exploration of sex differences in response to pharmacologic agents to investigations of gender differences in drug reinstatement in rodents, craving in humans and gender-specific treatment paradigms. Component #1: Sex Differences in an Animal Model of Relapse: Dr. Ronald See, an experienced pharmacologist, will be exploring gender differences in several well-developed animal models of drug self-administration reinstatement. Component #2: Gender Differences in Response to Cues in Cocaine Dependence: Dr. Kathleen Brady will lead this study of gender differences in response to cocaine-related cues and negative emotional states in men and women. This study will take place in the GCRC and involves the measurement of HPA axis response as well as autonomic and subjective response. Component #3: Gender, Menstrual Cycle and Smoking Cue Reactivity: Dr. Himanshu Upadhyaya will conduct a project studying the effect of menstrual cycle on the reactivity to nicotine and negative affect cues in humans. Component #4: Gender Influence on Preclinical Alcohol Pharmacology: Dr. Larry Middaugh will be using a rodent model to investigate the impact of gender and estrus state on the rewarding effects of ethanol and ethanol-conditioned stimuli. Component #5: Vocational Training for Drug-Dependent Women. Dr. Carrie Randall, the Co-PI of this project, will lead the research team of nurses and an experimental psychologist in this applied research project investigating gender-specific vocational services programs in unemployed recovering substance abusing women. This is an opportune time to develop a focused effort on research in women's health at MUSC. In terms of the thematic focus of the proposed SCOR, there is a convergence of opportunities and expertise in translational research in neuroscience and addiction. A cadre of talented and experienced basic scientists and clinical researchers from throughout MUSC interested in the SCOR has emerged and interdisciplinary collaboration and communication has been established. There is strong support from the leadership of MUSC. The focus on women's health and substance use disorders is sorely needed and complements many of the ongoing University efforts. Thus, the timing and thematic focus seem to ideally support the development of a Specialized Center of Research on Sex and Gender Factors Affecting Women's Health at MUSC.

substance abuse related behavior; cocaine; cues; drug addiction; drug abuse therapy; gender difference; drug /alcohol abstinence; drug abuse prevention; relapse /recurrence; behavioral /social science research tag; human subject; clinical research;

sertraline; posttraumatic stress disorder; human therapy evaluation; mental disorder chemotherapy; alcoholism /alcohol abuse chemotherapy; alcoholism /alcohol abuse; drug screening /evaluation; craving; hypothalamic pituitary adrenal axis; neurobiology; clinical trials; cues; outcomes research; comorbidity; patient oriented research; clinical research; human subject;

The Clinical Trials Network (CTN) is a cooperative agreement between NIDA, treatment providers and researchers throughout the nation in which science is being utilized as a vehicle to improve the treatment of addictions. In the initial funding period, a valuable infrastructure with bidirectional communication between the treatment and research communities was established and a number of important clinical trials were conducted. The SC Node has been an enthusiastic and productive participant in these activities. In this proposal, the progress of the last four years and a plan for future activities is described. Over the next five years, we will continue to work closely with NIDA and colleagues nationwide in conducting rigorous, multi-site clinical trials and improving CTN efficiency. We will extend our efforts in important ways. The SC Node will be the Lead Node for a pharmacotherapy/depression (CTN0026) study awaiting implementation. We will extend our geographical reach by forming a consortium of CTPs from South Carolina, Georgia and Mississippi to facilitate dissemination efforts. We will add a research CTP from a large urban area (Atlanta, Georgia) to expand the diversity and volume of potential research participants. We will use the CTN as a platform for research by seeking non-CTN funding (i.e., pharmaceutical or other federal funds) to support studies to be conducted across several CTN sites. We will extend the use of the CTN as a platform for training by partnering with minority training initiatives and other training programs at MUSC. The specific aims of this proposal are: (1) To work collaboratively with NIDA, the newly established coordinating and data centers, and other CTN Nodes in improving the efficiency of CTN operations, conducting and directing multi-site clinical trials and dissemination efforts. (2) To form a consortium of CTPs throughout South Carolina, Georgia and Mississippi to facilitate the dissemination of evidence-based practice in the substance abuse area. (3) To increase the utilization of the CTN as a research platform by applying for monies from non-CTN sources. We will conduct/participate in at least three studies using the CTN as a research platform during the renewal period. (4) To increase the use of the CTN .as a training platform by partnering with existing research training programs at MUSC. We will involve at least one new trainee per year and apply for at least one minority supplement. (5) To promote the use of the CTN as a platform for genetics research. We have applied for funding for a pharmacogenetics study to be conducted within the CTN. The CTN provides a unique and exciting opportunity to work collaboratively with colleagues throughout the nation in bridging the gap between research and treatment, and in exploring effective treatments for individuals with substance use disorders. The SC Node is enthusiastic about continuing its active role in the CTN over the next five years.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Physicians with in-depth experience and formal training in research design, development, implementation, statistical analysis, and interpretation of scientific information are said to be a "rare species" (NIMH, 1999). In the area of addictions research, the shortage of physicians trained in basic neurobiological and translational research, and in particular psychiatrists who are committed to careers as investigators, is at crisis proportions (NIDA, 2004). Physician scientists will be critical in translating advances in neuroscience into clinical interventions that can improve drug abuse treatment. This application describes a research training program designed to increase the number of physician-scientists with the skills to conduct patient-oriented research in the drug abuse area. The Medical University of South Carolina (MUSC) Drug Abuse Research Training (DART) program is a continuum of educational opportunities beginning in medical school and continuing in psychiatric residency. Program components target medical students and general psychiatry residents. Experiences are designed to attract, train, and advance participant's careers as independent investigators in patient-oriented drug abuse research. A coordinated curriculum, research experience, and "hands on" rotations are provided in support of effective research training to help recruit and prepare physicians to conduct research with individuals with substance use disorders. The specific aims of this application are: (1) To incorporate a drug abuse research training program within a 4-year psychiatry residency program for physicians committed to pursuing clinical research careers in the area of substance use disorders. (2) To enhance the didactic education of non-DART psychiatry residents in the parent program by increasing exposure to cutting-edge clinical research in the addictions field. (3) To extend participant recruitment into earlier phases of medical training by offering summer research jobs to first-year medical students and a clinical rotation elective in addictions research to fourth-year medical students. The DART program will provide the infrastructure and organizational support necessary to allow us to develop a continuum of programs designed to help increase the number of physician scientists focused on drug abuse research. This program is responsive to NIDA PAR-04-054 Research Education Grants In Drug Abuse and Addiction. The research education plan is consistent with recent recommendations of national consensus panels and builds on the experience of well-established research workforce development programs in the U.S. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This proposal focuses on a planning process to develop an academic home for clinical and translational science as a discipline and transform the way in which clinical and translational researchers are trained and supported at the Medical University of South Carolina (MUSC). MUSC currently has a diverse portfolio of clinical and translational research activities, including an NIH-funded GCRC and interdisciplinary Roadmap T32 Program. The planning activities will bring together individuals with substantial clinical, basic science, administrative and community outreach expertise from MUSC and other institutions in the state. The highest level of MUSC leadership will be integrally involved as well as political and business leaders from throughout the state. The planning activities will be co-directed by two physician-scientists who are well-established translational researchers and exemplary mentors. Oversight and integration will be provided by an Institutional Planning Committee composed of researchers and administrative leaders with the experience, enthusiasm and authority to prioritize and implement the changes needed to transform the culture and infrastructure to achieve the overall objective. The planning period has 3 phases spanning 18 months (needs assessment, plan integration, and implementation). The university has committed institutional funds to support planning activities prior to the potential award date, and for supplemental support during the anticipated award period. The following approaches will be utilized-analysis of strategic strengths, weakness, opportunities, and threats (SWOT); work groups who will conduct a needs assessment and develop concrete recommendations in 12 focal areas; and expert consultation from a professional consulting firm in organization planning and change management as well as academic/scientific leaders in clinical and translational research from other organizations that are at amore advanced level of clinical and translational research development and implementation. The specific aims of this proposal are to: (1) Identify the optimal structure and infrastructure for the CTSA at MUSC; (2)Assess resources and needs that are critical to develop and sustain clinical and translational research as a discipline with a true academic home at MUSC; (3) Design new programs or services to address critical needs identified in the planning process, (4) Integrate existing resources to enhance the clinical and translational activities of MUSC and the institutions, agencies and clinical networks with which we collaborate locally, statewide, and nationally. A milestone of the planning process is submission of a competitive CTSA U54 proposal. Our plan includes assessments designed to facilitate and evaluate cultural and organizational change on an ongoing basis. The development and subsequent implementation of the strategic plan has the potential to transform the research enterprise of MUSC and the state. [unreadable] [unreadable] [unreadable]

There is growing consensus that optimizing treatment outcomes for substance use disorders may be achieved through careful integration of pharmacologic and psychosocial interventions. Working closely with Project 3 for the identification of compounds, the proposed project will assess the ability of select pharmacotherapeutic agents to augment the therapeutic effects of a cue exposure intervention for methamphetamine (METH) dependence and to preliminarily assess impact on measures of cognitive functioning. D-cycloserine (DCS), a partial glutamate agonist facilitates associative learning, is one agent likely to be explored and has been chosen as the prototype for this application. The specific aims are: 1. To develop a set of environmental cues specific to METH use;2. To investigate the ability of the METH-specific cues to elicit craving and physiological reactivity in METH-dependent individuals;3. To explore the impact of DCS on response to METH-related cues;and 4. To preliminarily explore the relationship of cognitive function to DCS response in METH dependent individuals. We will initially develop methamphetamine cues through conducting interviews with METH dependent individuals and pilot testing to assess the ability of the cues developed to provoke craving and physiologic response. In vivo, picture and video cues will be developed within the first six months. In parallel, a Virtual Reality METH cue environment will be developed to be used in future studies. After a satisfactory set of cues has been developed, METH-dependent individuals will be recruited to receive either DCS or a placebo prior to each of two, one-hour exposure sessions in which drug use and other drug-related stimuli will be presented using in vivo and video cue presentation. Multiple assessments of craving and physiologic reactivity will be obtained during and after the cue exposure sessions and during an unmedicated test session one-month after the second cue exposure session. The primary outcome measures will be subjective (craving, desire to use) and physiologic (heart rate, skin conductance) responses to METH cues. In summary, this pilot project will begin with the development of METH-related environmental cues to be used both in this project and Project 2. Guided by the findings of Project 3, the use of innovative pharmacologic approaches to the treatment of METH dependence through the facilitation of extinction of responses to METH conditioned cues will be explored. The impact of pharmacologic agents on cognitive function in METH dependent individuals will also be preliminarily explored. Through working closely with the other center studies, methodology will be developed and pilot data generated to guide a P50 application.

DESCRIPTION (provided by applicant): Over the last four years, the Medical University of South Carolina's (MUSC) Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women's Health has functioned as a productive interdisciplinary research center focused on treatment and relapse in substance use disorders in women. When the MUSC SCOR was established in 2002, it filled an important gap. While MUSC had significant depth and strength in translational, interdisciplinary research in the area of substance use disorders, there was no gender-specific focus. Furthermore, the MUSC SCOR was the first women's health research initiative to be undertaken on the MUSC campus. The active, campus-wide collaborations of SCOR investigators, combined with the SCOR pilot project program have encouraged and impacted gender-based research campus-wide. During the renewal period, we propose to more closely link our scientific projects and follow up on intriguing findings from the previous funding period. Each core research project will involve the investigation of the biological basis of sex differences in drug abuse reinstatement, craving and/or relapse, and treatment implications. The overarching goals of the center will focus not only on supporting and maximizing the translational scientific collaborations of the core and pilot research projects, but also on continuing to catalyze the growth of gender-based research throughout the MUSC campus. The Specific Aims for the years 6-10 of the MUSC SCOR are: Specific Aim #1: To continue the well-established, multi-disciplinary, translational program of research focused on gender-related issues in substance use disorders at MUSC. Specific Aim #2: To provide common resources through the Administrative Core to assist investigators in increasing efficiency, maximizing scientific rigor and productivity, and collecting pilot data. Specific Aim #3: To encourage and support the growth of gender-based research throughout the MUSC campus. Specific Aim #4: To attract and mentor young investigators and new faculty in the area of research, particularly patient-oriented research, in women's health issues. Specific Aim #5: To provide a regional education and training resource for research in women's health research.

Relapse to drug abuse following abstinence is a significant impediment in the treatment of cocaine dependence. Although various factors (stress, conditioned cues, drugs) that contribute to relapse have been studied in males, the impact in females has been less explored. We have recently shown sex differences for conditioned cue-induced and drug-primed reinstatement of cocaine-seeking in an animal model of relapse. Moreover, the differences seen in females are closely linked to the estrus phase of the estrous cycle. Building on these previous studies, this SCOR project will provide a comprehensive approach to examine sex and estrous cycle dependent differences in reinstatement of cocaine-seeking produced by various trigger factors. Using direct pharmacological activation of the neural pathways that mediate stress responses (e.g., ascending noradrenergic pathways and corticotropin-releasing factor receptors) we predict that female rats (particularly during the estrus phase) will show greater reinstatement of cocaine-seeking than male rats exposed to the same stressor. The use of the exact same stressors and cue reactivity approaches in both the animal model and the human clinical laboratory (SCOR Project #2),will provide a high degree of homology and integration. Following characterization of stress and stress+cue induced reinstatement in males and females, we will examine sex and estrous cycle dependent pharmacotherapy interventions that will attenuate relapse, specifically: a) clonidine, a noradrenergic receptor agonist that may selectively block stress-induced reinstatement;b) progesterone, an ovarian hormone that we have recently found to be inversely related to cocaine-seeking in females;and c) aripiprazole, a novel dopamine receptor partial agonist that blocks cue and drug-primed reinstatement in males, but has never been tested in females. The information gained from these studies will integrate with the clinical SCOR projects that will focus on gender differences and relapse in cocaine (Project #2) and nicotine (Project #4) dependent women andmen, including the relationship of ovarian hormones to drug-seeking. In addition, this project will parallel the preclinical animal model of sex and estrous cycle dependent differences in nicotine-seeking and reinstatement in Project #3. This preclinical animal model of relapse will characterize fundamental sex and estrous cycle dependent differences in cocaine-seeking behavior produced by known risk factors for relapse in humans (i.e., stress, cues, drugs). Furthermore, we will assess pharmacotherapies that may be generalized across males and females, as well as interventions that may be gender-specific. The results from these studies will help identify promising pharmacotherapeutic agents for future testing in the human laboratory setting.

Administrative Core The Administrative Core (AC) is the backbone of MUSC SCOR operations. Throughout the previous funding periods, the AC facilitated work of the SCOR investigators by providing an organizational framework for supporting research productivity, addressing emergent issues, and coordinating daily operations. The AC provides (1) defined physical space, (2) unambiguous leadership, (3) a clear management structure, (4) administrative, biostatisitcal, research support, and fiscal services, (5) a means for ongoing communication, integration, and quality control, (6) a structure for training and research activities, and (7) coordination and supervision of the pilot project program. It insures the integration of the SCOR within MUSC, with local and statewide officials, and with community treatment centers. During this funding period, the AC will take on additional duties to coordinate an annual MUSC Sex and Gender Research Day as well as an increasing number of community 'outreach activities and cross-SCOR collaborations. Additionally, the AC has developed and implemented internal and external quality control mechanisms to insure that the MUSC SCOR and the AC are accomplishing their goals. The AC will continue to use the administrative structure and many of the same operational procedures that have worked well for the past nine years in the next funding period.

There are likely to be gender differences in relapse to drug use following abstinence in cocaine-dependent individuals. In our current SCOR human laboratory study, gender differences in the response to a social stressor and cocaine cues in cocaine-dependent individuals has been demonstrated. Additionally, work from another current MUSC SCOR project has demonstrated sex differences in response to cocaine-conditioned cue and cocaine-primed reinstatement in animal models which was correlated with reduced plasma progesterone levels. Although gender differences in factors such as stress and conditioned cues that contribute to relapse in cocaine-dependent individuals have been studied independently, the interaction of stress and cues and the effect of hormonal status on response has not been directly explored. The proposed study will build on the work done during the last funding period by studying the role of hormonal status on the response to cocaine-related cues with or without stress in cocaine-dependent women and men. This project will also be important in extending an animal model of pharmacologically-induced stress (yohimbine-induced stress) to a human laboratory setting. As such, this project will use the exact same stressor as the proposed synergistic basic science project (Project 1), providing a high degree of homology and integration. This project will further the ability to directly translate findings from an animal model of relapse to an ecologically valid test of relapse in cocaine-dependent humans and explore the impact of hormonal status on response in this model. As a further integration of the research focus between SCOR projects, both this study and Project 4 will explore the relationship between impulsivity and craving. The specific aims of this project are:1. To determine the interaction of a pharmacological stressor with exposure to cocaine-related cues and the impact of ovarian hormone status on this response in women;2. To explore the relationship between impulsivity, stress, and cocaine craving in cocaine-dependent men and women;and 3. To explore the relationship between the DHEA/cortisol ratio and response to a pharmacologic stressor in control and cocaine-dependent men and women. The interaction of stress and cues has not been systematically investigated although this paradigm closely mirrors real-life situations. Animal studies suggest that gonadal hormones play a role in the subjective and reinforcing effects of stimulants, but their role in cue or stress-induced craving has not been explored. In addition, there are important sex differences in the impact of stress on cognition that appear to be related to gonadal hormones. Sex differences in the cognitive response to stress, including increased impulsivity, may be important in the relationship between stress, cocaine cues and craving.

[unreadable] DESCRIPTION (provided by applicant): The overall objective of the MUSC BIRCWH Program Is to promote the performance of research in women's health by bridging advanced training with research independence. The Interdisciplinary Women's Health Research program at MUSC will encourage interdisciplinary study of differences between women and men that impact the prevention, diagnosis and treatment of disease in two major focus areas - Aging and Mental Health. The convergence at MUSC of substantial expertise in these two critical areas assures our ability to mentor junior faculty to study women's health issues across the lifespan. Our faculty mentors have a broad skills basis in both aging and mental health, especially pertaining to dementia, substance use disorders, PTSD, and depression. In addition, we have specific expertise in the study of gender differences in pharmacokinetics, pharmacodynamics, and pharmacogenomics. The BIRCWH training consists of: (1) intensive mentored research experiences designed to prepare outstanding junior faculty to become independent investigators in women's health research; (2) specific didactic course-work in order to provide a strong, comprehensive base of relevant knowledge and skills; (3) regularly scheduled seminars and journal clubs in women's health research, in order to promote information exchange and interdisciplinary interaction in the context of current findings and new implications; (4) ongoing activities providing continuing review and consultation in critical areas in order to ensure continuous learning, sound judgment, and awareness of changing dynamics in scientific research; (5) additional opportunities to participate in thematic or topical exchanges with other interdisciplinary research groups at MUSC pertinent to the Scholars' chosen research interest(s) in order to extend Scholars' interdisciplinary perspective on women's health research and expand networking opportunities for future collaborations; and (6) a comprehensive evaluation plan utilizing formative and summative techniques as well as formal and informal approaches for reviewing and evaluating both Scholar progress and program effectiveness in order to provide outstanding mentoring in research relevant to women's health. [unreadable] [unreadable] [unreadable] [unreadable]

Nicotine addiction, in the form of cigarette smoking, is the leading preventable cause of morbidity and mortality in the US. Although the prevalence of smoking has decreased substantially in the last few decades, it remains the single most prevalent form of addictive behavior. A growing body of research has shown that stimuli associated with nicotine administration (e.g., sight and odor of a cigarette) gradually acquire the capacity to elicit craving (urge to smoke) and other physiological responses (e.g., heart rate changes) that are presumed to contribute to the maintenance of smoking behavior. Recent research suggests that gender and intra-gender factors, such as menstrual cycle phase in women, may modulate the craving and physiological reactions elicited by smoking cues. Relatedly, the findings of our on-going SCOR protocol suggest that men and women may differ in their craving and physiological reactions to smoking and stress cues, and that these same reactions may differ among women smokers who are in different phases of their menstrual cycle. Additionally, a SCOR-funded pilot protocol has permitted us to establish procedures for, and determine the feasibility of, a study to manipulate the timing of quit attempts relative to menstrual cycle phase and to determine the impact on smoking cessation outcome. Building on our previous work, this application proposes a two-part research design, in which we first randomize 226 nicotine-dependent women aged 18-40 to receive a single-session, cue reactivity/impulsivity assessment in either the follicular or luteal phase of their menstrual cycle. In this session, standardized measures of cue reactivity and impulsivity will be obtained. Cue reactivity procedures will involve exposure to robust in vivo smoking cues and take place under conditions of nicotine deprivation. The second part of the study, using the same study sample, proposes a 2x2 randomized clinical trial, in which tinning of quit attempts (follicular vs. luteal menstrual cycle phase) is crossed with pharmacotherapy (transdermal nicotine patch vs. varenicline). Thus, our study represents a programmatic extension of our prior research on menstrual-related effects on smoking behavior, integrates a human laboratory cue-reactivity paradigm with a treatment outcome study, tests whether pre-treatment responses to smoking cues predict measures of treatment outcome, and examines potential interactions between timing of menstrual phase and type of treatment. This application fits well within the scope of the overall SCOR and specifically interdigitates with Component 3, which examines menstrual cycle effects on nicotine administration and reinstatement in a mouse model, and with Component 2, which examines cue-induced craving to cocaine in a clinical population. Results of this study may inform treatment-optimizing decision-making among women smokers.

Nicotine dependence is the leading preventable cause of mortality in the world today. Cue-induced craving is likely to play an important role in relapse. The neural correlates of smoking cue-induced craving and extinction have been elucidated using fMRI. Recent advances make it possible to utilize real-time fMRI (rtfMRI) feedback to modify behavior, cognitions and regional brain activity. The purpose of this proposal is to develop the imaging parameters, brain-computer interface and standardized procedures for using rtfMRI with visual feedback to help nicotine-dependent individuals decrease craving when presented with smoking cues. The exploratory nature of this study requires a phased approach. Phase 1 will focus on the development of the technology and study paradigm. In order to proceed to Phase 2, there must be convincing evidence that a substantial proportion of nicotine-dependent individuals can manipulate brain activity in critical brain regions associated with smoking cue-induced craving based on rtfMRI visual feedback. If this is established, a controlled comparison and duration of effect will be explored in Phase 2. This project will set the stage for clinical trials investigating a very innovative approach to the treatment of nicotine dependence and other substance use disorders. The study will provide critical information about optimal techniques, durability and transferability of the effects to situations outside of the scanner. The findings of this study can be used to inform the design of a clinical trial to investigate the use of rtfMRI neuromodulation training in smoking cessation.

(+-)-1-(3-Chlorophenyl)-2-((1,1-dimethylethyl)amino)-1-propanone; 21+ years old; Adolescent; Adolescent Youth; Adult; Age; American; Amfebutamone; Area; Behavior Conditioning Therapy; Behavior Modification; Behavior Therapy; Behavior Treatment; Behavior or Life Style Modifications; Behavioral Conditioning Therapy; Behavioral Modification; Behavioral Therapy; Behavioral Treatment; Bupropion; CRISP; Cause of Death; Cessation of smoking; Cigarette Smoker; Combination Medication; Computer Retrieval of Information on Scientific Projects Database; Conditioning Therapy; Daily; Drugs; Drugs, Illicit; Funding; Grant; Health; Human, Adult; Illicit Drugs; Individual; Institution; Investigators; Life Style Modification; Medication; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nicotine; Outcome; Pharmaceutic Preparations; Pharmaceutical Preparations; Public Health; Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S)-; Rate; Research; Research Personnel; Research Resources; Researchers; Resources; Smoke; Smoker; Smoking; Social Welfare; Source; Testing; Tobacco; United States; United States National Institutes of Health; adult human (21+); behavior intervention; behavioral intervention; buproprion; cease smoking; cigarette smoking; contingency management; day; drug/agent; high school; improved; juvenile; juvenile human; public health medicine (field); smoke cigarette; smoking cessation; welfare

DESCRIPTION (provided by applicant): Emerging data supports the role of glutamate in extinction learning. D-cycloserine (DCS), a partial glutamate agonist, facilitates extinction of associative learning in animal models of fear-conditioning and clinical studies of exposure treatment for anxiety disorders. A recent study demonstrated DCS acceleration of extinction of cocaine-induced conditioned place preference in rats. The proposed study will extend these innovative and promising findings from the basic science arena and anxiety disorders field in a proof of concept investigation of DCS facilitation of extinction of response to cocaine-related cues in a human laboratory paradigm. The specific aims of this application are: 1. To explore the impact of acute administration of D-cycloserine (DCS) on response to cocaine-related cues in cocaine-dependent individuals. 2. To explore the impact of number of doses and schedule of DCS administration on the extinction of response to cocaine-related cues in cocaine-dependent individuals. 3. To preliminarily explore the durability of DCS-facilitated extinction of response to cocaine-related cues it is hypothesized that the administration of DCS before cocaine cue exposure sessions will decrease cocaine craving and physiologic reactivity in response to cocaine-related cues. To test the hypotheses, 72 cocaine- dependent individuals will be randomized to DCS or placebo administration before three one-hour cocaine cue exposure sessions over a seven-day period. Cue exposure sessions will be held on days one, four and seven. One group will receive DCS (50 mg) before each session;one group will receive DCS (50 mg) before sessions on days one and seven and placebo before the day four session;one group will receive placebo before all three sessions. Multiple assessments of craving and physiologic reactivity will be obtained during and after each session. Primary outcome measures will be subjective and physiologic response to cocaine cues. A follow-up cue exposure session will be conducted one week after the third exposure session to assess durability of effect. Cocaine craving, self-report of cocaine use and a UDS will be collected. In summary, this pilot, proof of concept study will explore the application to addictions of an innovative treatment approach which has shown promise in the treatment of anxiety disorders. Exposure-based treatments in the addictions field are supported by animal models and have broad theoretical support, but the translation into clinical practice has been disappointing. Successful pharmacologic facilitation of extinction of response to drug-related cues may reinvigorate research on exposure-based treatment for addictions. If DCS proves successful in this preliminary study, further trials exploring the parameters of the DCS effect will be planned. Future studies could explore the impact of DCS on the generalizability or persistence of extinction training which could greatly enhance the clinical applicability of exposure-based treatments. New treatments are needed for cocaine dependence. Cocaine-related environmental cues are likely to be involved in relapse. In this study, an innovative pharmacologic approach to decreasing the response to cocaine cues will be tested.

The goal of the South Carolina Clinical and Translational Research Institute (SCTR) is to create a sustainable home at the Medical University of South Carolina (MUSC) to advance clinical and translational research as a distinct discipline and facilitate collaboration across multiple disciplines. The overall approach focuses on: (1) implementing important advances in biomedical science to create opportunities for discovery, (2) removing barriers to facilitate the linkage of knowledge, experience and expertise across disciplinary boundaries, (3) providing training and mentoring experiences to enhance the pipeline for clinical and translational researchers with diverse training and backgrounds, and (4) fostering community engagement with a rapidly growing statewide population that is underserved by many systems to improve their participation and health outcomes. MUSC has long-standing experience leading successful clinical and translational research efforts that span the state. It is the leading state institution in extramurally funded research activities and has a rich research training portfolio. SCTR was established in 2007 with the vision that it would be the "agent of change" in transforming the research culture at MUSC and statewide via strong relationships with academic and community-based affiliates. Great progress has already been made including the development of an institutional K12 Career Development Program in Clinical and Translational Research, implementation of a pilot project program that funded 29 projects in the first two competitive rounds, and establishment of a robust collaboration with the NIH-funded CTSA at Vanderbilt University for assistance in the SCTR Biomedical Informatics Program. Joining the national CTSA Consortium will accelerate progress by further facilitating (1) development and interoperability of biomedical informatics systems, (2) active exchange of best processes and best practices in evidence-based medicine and community engagement, (3) advancement of clinical and translational science as a discipline and career path;and (4) shared knowledge, experience and collective influence in setting regional and national research agendas and health policy designed to generate the transformative results envisioned by the NIH Roadmap. RELEVANCE (See instructions): SCTR will bring together scientists, clinicians and the lay community to address diseases that commonly impact the citizens of South Carolina. SCTR will coordinate resources and expertise statewide in efficient, innovative approaches to research. Through SCTR, a new generation of researchers will be trained to work across multiple disciplines in collaboration with community members so that scientific discovery is relevant anri ranifllv fran.slaffid tn frnnt-linFt treafnnRnt .qeffinn.s for maximum imnant nn hftalth niifrnmes.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of the South Carolina Clinical and Translational Research Institute (SCTR) is to create a sustainable home at the Medical University of South Carolina (MUSC) to advance clinical and translational research as a distinct discipline and facilitate collaboration across multiple disciplines. The overall approach focuses on: (1) implementing important advances in biomedical science to create opportunities for discovery, (2) removing barriers to facilitate the linkage of knowledge, experience and expertise across disciplinary boundaries, (3) providing training and mentoring experiences to enhance the pipeline for clinical and translational researchers with diverse training and backgrounds, and (4) fostering community engagement with a rapidly growing statewide population that is underserved by many systems to improve their participation and health outcomes. MUSC has long-standing experience leading successful clinical and translational research efforts that span the state. It is the leading state institution in extramurally funded research activities and has a rich research training portfolio. SCTR was established in 2007 with the vision that it would be the "agent of change" in transforming the research culture at MUSC and statewide via strong relationships with academic and community-based affiliates. Great progress has already been made including the development of an institutional K12 Career Development Program in Clinical and Translational Research, implementation of a pilot project program that funded 29 projects in the first two competitive rounds, and establishment of a robust collaboration with the NIH-funded CTSA at Vanderbilt University for assistance in the SCTR Biomedical Informatics Program. Joining the national CTSA Consortium will accelerate progress by further facilitating (1) development and interoperability of biomedical informatics systems, (2) active exchange of best processes and best practices in evidence-based medicine and community engagement, (3) advancement of clinical and translational science as a discipline and career path;and (4) shared knowledge, experience and collective influence in setting regional and national research agendas and health policy designed to generate the transformative results envisioned by the NIH Roadmap. RELEVANCE (See instructions): SCTR will bring together scientists, clinicians and the lay community to address diseases that commonly impact the citizens of South Carolina. SCTR will coordinate resources and expertise statewide in efficient, innovative approaches to research. Through SCTR, a new generation of researchers will be trained to work across multiple disciplines in collaboration with community members so that scientific discovery is relevant

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of the South Carolina Clinical and Translational Research Institute (SCTR) is to create a sustainable home at the Medical University of South Carolina (MUSC) to advance clinical and translational research as a distinct discipline and facilitate collaboration across multiple disciplines. The overall approach focuses on: (1) implementing important advances in biomedical science to create opportunities for discovery, (2) removing barriers to facilitate the linkage of knowledge, experience and expertise across disciplinary boundaries, (3) providing training and mentoring experiences to enhance the pipeline for clinical and translational researchers with diverse training and backgrounds, and (4) fostering community engagement with a rapidly growing statewide population that is underserved by many systems to improve their participation and health outcomes. MUSC has long-standing experience leading successful clinical and translational research efforts that span the state. It is the leading state institution in extramurally funded research activities and has a rich research training portfolio. SCTR was established in 2007 with the vision that it would be the "agent of change" in transforming the research culture at MUSC and statewide via strong relationships with academic and community-based affiliates. Great progress has already been made including the development of an institutional K12 Career Development Program in Clinical and Translational Research, implementation of a pilot project program that funded 29 projects in the first two competitive rounds, and establishment of a robust collaboration with the NIH-funded CTSA at Vanderbilt University for assistance in the SCTR Biomedical Informatics Program. Joining the national CTSA Consortium will accelerate progress by further facilitating (1) development and interoperability of biomedical informatics systems, (2) active exchange of best processes and best practices in evidence-based medicine and community engagement, (3) advancement of clinical and translational science as a discipline and career path;and (4) shared knowledge, experience and collective influence in setting regional and national research agendas and health policy designed to generate the transformative results envisioned by the NIH Roadmap. RELEVANCE (See instructions): SCTR will bring together scientists, clinicians and the lay community to address diseases that commonly impact the citizens of South Carolina. SCTR will coordinate resources and expertise statewide in efficient, innovative approaches to research. Through SCTR, a new generation of researchers will be trained to work across multiple disciplines in collaboration with community members so that scientific discovery is relevant

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of the South Carolina Clinical and Translational Research Institute (SCTR) is to create a sustainable home at the Medical University of South Carolina (MUSC) to advance clinical and translational research as a distinct discipline and facilitate collaboration across multiple disciplines. The overall approach focuses on: (1) implementing important advances in biomedical science to create opportunities for discovery, (2) removing barriers to facilitate the linkage of knowledge, experience and expertise across disciplinary boundaries, (3) providing training and mentoring experiences to enhance the pipeline for clinical and translational researchers with diverse training and backgrounds, and (4) fostering community engagement with a rapidly growing statewide population that is underserved by many systems to improve their participation and health outcomes. MUSC has long-standing experience leading successful clinical and translational research efforts that span the state. It is the leading state institution in extramurally funded research activities and has a rich research training portfolio. SCTR was established in 2007 with the vision that it would be the "agent of change" in transforming the research culture at MUSC and statewide via strong relationships with academic and community-based affiliates. Great progress has already been made including the development of an institutional K12 Career Development Program in Clinical and Translational Research, implementation of a pilot project program that funded 29 projects in the first two competitive rounds, and establishment of a robust collaboration with the NIH-funded CTSA at Vanderbilt University for assistance in the SCTR Biomedical Informatics Program. Joining the national CTSA Consortium will accelerate progress by further facilitating (1) development and interoperability of biomedical informatics systems, (2) active exchange of best processes and best practices in evidence-based medicine and community engagement, (3) advancement of clinical and translational science as a discipline and career path;and (4) shared knowledge, experience and collective influence in setting regional and national research agendas and health policy designed to generate the transformative results envisioned by the NIH Roadmap. RELEVANCE (See instructions): SCTR will bring together scientists, clinicians and the lay community to address diseases that commonly impact the citizens of South Carolina. SCTR will coordinate resources and expertise statewide in efficient, innovative approaches to research. Through SCTR, a new generation of researchers will be trained to work across multiple disciplines in collaboration with community members so that scientific discovery is relevant

DESCRIPTION (provided by applicant): Since 2000, the Southern Consortium Node (SCN) has worked closely with community partners and colleagues nationwide in research and dissemination activities designed to improve the treatment of addictions through research and implementation of evidence-based practice. In this renewal application, the SCN proposes to expand to include a broader region of the southeast through partnership with Duke University, a national leader in medical research. Duke University is an ideal partner because of their complementary scientific expertise, strong primary care and HIV research activities, geographic proximity and prior experience with CTN activities. The partnership will extend the SCN's regional and geographic distribution to span a large portion of the Southeastern US and bring close connections with well-established primary care and HIV clinical research networks to broaden the types of clinical settings and patient populations available for CTN trials. The SCN will establish a robust collaboration with the CTSA initiative through a number of individuals who will serve as investigators on both the CTN and CTSA, including Dr. Brady who is the PI of the MUSC CTSA. The primary specific aims for the next five years are: to extend the geographic reach of the SCN to include CTPs and academic partners in South Carolina, North Carolina, Georgia, Tennessee and Mississippi. To develop research sites in primary care and medical specialty clinics that will expand the diversity of and number of participants available to participate in CTN trials. To increase the use of CTN as a training platform and a research platform for non-CTN research. To develop a robust collaboration between the CTN and both local and national CTSAs for the purpose of bidirectional sharing of "best-practices", informatics and trial design strategies across networks. To expand the scientific expertise available to the CTN through partnership of investigators at MUSC and Duke University. PUBLIC HEALTH RELEVANCE: The CTN is a cooperative agreement between NIDA, treatment providers and researchers throughout the nation in which science is being utilized as a vehicle to improve the treatment of addictions. It is the goal of the SCN to work collaboratively with NIDA, the newly established coordinating a data centers, and other CTN Nodes in conducting and directing multi-site clinical trials and dissemination efforts.

DESCRIPTION (provided by applicant): Substance use disorders (SUDs) are complex diseases with biopsychosocial underpinnings and multiple medical sequel that are best addressed by multidisciplinary teams of diverse individuals in the treatment and research realms. This proposal requests continued support of a grant (R25 DA020537) that was used to develop and implement several innovative programs, collectively known as the Drug Abuse Research Training (DART) programs, designed to increase the number of clinician-scientists committed to pursuing clinical research careers in the area of SUDs at the Medical University of South Carolina (MUSC). In the original project period, DART programs targeted psychiatry residents and medical students. In the renewal period, we propose to build on the success of the existing programs by expanding and diversifying the trainees involved in DART programs in strategic directions that align with the priorities of NIDA and the need for interdisciplinary team work that is mandated by the complexities of the patient population with SUDs. The specific aims of the proposed research education training program are: 1) To continue to attract and train psychiatry residents committed to pursuing research careers focused on patient-oriented research in addictions;2) To transform the DART Summer Research Fellowship for medical students into an interdisciplinary training program by including trainees from the Colleges of Nursing, Dental Medicine and Pharmacy;3) To partner with the existing MUSC Summer Undergraduate Research Program (SURP) to offer a clinical research training experience focused on SUDs to select undergraduate students;4) To partner with the training and training evaluation programs within the MUSC Clinical and Translational Science Institute (UL1 RR029882) so that DART trainees will benefit from CTSA educational resources and addiction research will gain increased visibility across the MUSC campus;5) To conduct targeted outreach to under-represented minority trainees in all of the DART programs. The multidisciplinary training and partnerships with campus-wide training and research initiatives proposed will facilitate the collaborative clinical and research initiatives that will be necessary to meet critical workforce development needs and move the recognition and treatment of addictive disorders into the mainstream of medical practice. PUBLIC HEALTH RELEVANCE: The participation of clinician-scientists in the biomedical research enterprise helps bridge the gap between basic science and clinical practice to address the healthcare needs of the public. In recent years the number of physicians engaged in research careers has declined by more than half, as have the number of research psychiatrists and research fellowships for psychiatrists. Interdisciplinary training focused on substance abuse disorders (SUDs) should facilitate the collaborative clinical and research initiatives that will be necessary to move the recognition and treatment of addictive disorders into mainstream medical practice.

Project I: Oxytocin and Cocaine Dependence Co-Principal Investigators: Kathleen Brady and Aimee McRae-Clark; Co-Investigators: Jane Joseph, Megan Moran-Santa Maria Response to stress may be important in understanding sex/gender differences in drug dependence and may also be a target for developing both psychotherapeutic and pharmacotherapeutic interventions. Our previous SCOR work has suggested that the HPA axis in women may be more sensitive to the toxic effects of cocaine or early life trauma as compared to men; furthermore, cocaine-dependent women have a greater physiologic and subjective response to stress and the magnitude of this response may be related to the potential for relapse. As such, therapies focused on modulation of the stress response might be particularly important for women. Oxytocin is a hypothalamic neuropeptide that has been shown to mediate behavioral responding to stress as well as play a role in neuroadaptations that occur as a consequence of long-term drug use. Given these effects, oxytocin may have a therapeutic role in ameliorating the negative affect commonly observed prior to relapse in cocaine-dependent individuals. As estrogen appears to enhance oxytocin's effects, women may have an enhanced response to oxytocin. We propose an evaluation of the impact of oxytocin on the endocrine, physiological and subjective response to a validated laboratory stressor (the Trier Social Stress Task) in cocaine-dependent men (n=76) and women (n=76). In addition, fMRI will be used to evaluate the impact of oxytocin on functional brain activity in limbic and striatal nuclei during a cue- reactivity task and to assess gender differences in the neural response to oxytocin. The impact of estrogen and progesterone on stress and cue reactivity will also be measured. To our knowledge, this will be the first clinical investigation of oxytocin in cocaine-dependent individuals. Consistent with the overall theme of the MUSC SCOR, this project will directly explore the mechanistic underpinnings of the stress response in cocaine dependent men and women, and provide important data on a potential treatment approach. RELEVANCE (See instructions): Stress is likely involved in relapse to cocaine use. This project will investigate the role oxytocin may play in the stress response in cocaine-dependent men and women and examine how oxytocin may impact brain activity in individuals exposed to cocaine-related cues.

Project IV: Gender, Sex Hormones and Stress-related Smoking (Saladin & Gray) Even with the use of evidence-based treatments, most smokers are unsuccessful when attempting to quit, and cessation rates are particulariy discouraging among women. Gender and sex hormone influences on the relationships between stress, craving, and smoking behavior may be key factors underiying this important health disparity. Recent laboratory findings support this assertion, but further work is needed to (a) measure and characterize the relationship between gender/sex hormones and craving experienced by female and male smokers in their real worid (i.e., non-laboratory) environment, (b) examine the relationship between gender/sex hormones and stress-induced changes in smoking behavior, and (c) examine the treatment potential of a novel pharmacological agent (oxytocin) that may address gender-relevant stress-responsive smoking behaviors. A mixed naturalistic and laboratory research strategy is proposed to address current gaps in knowledge. Over a two-week period, female and male smokers will provide daily saliva samples for measurement of sex hormones, and will ufilize a newly developed and validated software implemented on a personal digital assistant (iPhone) to provide real-fime responses to smoking-related and neutral picture cues presented mulfiple times daily in their day-to-day natural environment. Participants will then take part in a laboratory session that will examine the effects of oxytocin on stress reactivity and smoking behavior. Prior to the session, participants will abstain from smoking for 12 hours and provide a salivary sample for measurement of stress/sex hormones (Cortisol, estradiol, progesterone, testosterone) levels. Next, participants will receive either oxytocin or placebo and then be exposed to the Trier Social Stress Test (TSST). Measures collected at mulfiple fime points during the laboratory session will include: craving, stress, negative emofion, heart rate, blood pressure, skin conductance, and Cortisol. Afterthe TSST, participants will complete a smoking resistance task (SRT) in which they will receive a monetary reward for every 5-min period they resist smoking. After the SRT, participants will be allowed to smoke freely during a 1-hour ad libitum smoking period (ASP), with smoking topography assessed via a portable device. It is expected that, in real worid setfings, females will be more reacfive to smoking-related cues than male smokers, and that, among females, the ratio of estradiol to progesterone will be positively related to craving. In the laboratory, it is predicted that (a) females will evidence greater stress, craving, and smoking behavior, but less neuroendocrine (Cortisol) reactivity, to the TSST, and (b) oxytocin vs. placebo, will attenuate stress, craving, and Cortisol response to the TSST. Findings from the proposed study will substantially address a key gender-related health disparity, potenfially informing the development of gender-speciflc intervenfions to enhance female smokers' response to cessation treatments. Therefore, the knowledge to be gained may yield signiflcant public health benefits. RELEVANCE (See instructions): Cigarette smoking is arguably the single greatest preventable cause of morbidity and mortality. Importanfiy, women appear to have more difficulty quitting smoking than men. In an effort to increase understanding of this signiflcant health disparity, the proposed study will employ novel and established research methods to examine the (a) role of sex hormones in craving/stress factors that affect the smoking behavior of women and men, and (b) treatment potenfial of a new medicafion.

DESCRIPTION (provided by applicant): The establishment of the Medical University of South Carolina (MUSC) SCOR in 2002 provided a critical impetus to engage the research community in more sex and gender-based research. MUSC had strength in translational, interdisciplinary research addictions, but no sex or gender-specific focus. In addition, the SCOR was the first women's health research initiative on the MUSC campus. The visible, campus-wide collaborations of SCOR Investigators, combined with the Institutional support of the SCOR pilot project program have considerably increased sex and gender-based research. Close collaboration with the MUSC BIRCWH program, awarded in 2007, further enhanced campus-wide, interdisciplinary collaborations focused on women's health. We have begun collaborations with SCOR programs at other universities in order to maximize the scientific output from the ORWH investment in the SCOR initiative by sharing resources and combining data. During the renewal period, our core scientific projects will continue to focus on sex and gender differences in the relationship between addiction and stress response using emerging technology in closely aligned clinical and basic science projects. The overarching goals of the center will focus on supporting and Improving the translational scientific collaborations of the core and pilot research projects, catalyzing further growth of interdisciplinary sex and gender-based research on the MUSC campus and creating strategic partnerships to enhance the translation and dissemination of SCOR findings and other relevant research to improve the health of women and girls. Center funding has allowed us to: 1) increase interdisciplinary sex and gender-based research on the MUSC campus, 2) bring together institutional and scientific leadership to form a high visibility operational unit focused on research In women's health, 3) establish infrastructure to support efficient operations, integration, and stability, 4) coalesce a group of senior investigatos to integrate their scientific expertise and research skills to advance sex and gender-based research, 5) attract and train new and junior investigators in sex and gender-based research, 6) support the development and testing of innovative ideas and new technology, and 7) provide a supportive training environment for basic and clinical researchers interested In sex and gender-based research. The next funding period will allow us to build on these accomplishments, expand our research program utilizing innovative techniques and novel compounds, increase cross-SCOR collaborations, enhance outreach and dissemination efforts, and attract new investigators. Our SCOR, with a truly interdisciplinary and translational focus on sex and gender Issues in addictions and stress response, is prepared to work collaboratively with other SCOR colleagues towards the vision, goals, and objectives outlined In the 2010 ORWH Strategic Plan.

Project III: Stress Circuits and Sex Differences in Drug Seeking (Aston-Jones) There is growing evidence for a relationship between stress reactivity and substance use disorders that differ by gender. Brain norepinephrine (NE) and corticotropin releasing factor (CRF) systems are important in stress responses. Recent findings indicate a link between the sex/gender differences in drug abuse and these brain systems: LC-NE neurons in females are more responsive to stressors and to CRFI receptor activation than in males. In addition, oxytocin (OT) neurons are involved in reward processes, perhaps via interactions with NE and CRF, and may play a role in drug craving. In this project we will characterize the roles of these systems in sex/gender-specific drug seeking using behavioral pharmacology and Fos immunohistochemistry in rodent model of cocaine seeking. We hypothesize that sex differences in the CRF-NE system facilitate increased cocaine seeking in females; specifically, we propose that the stress of eariy abstinence increases CRF input to LC, and that the higher response of LC-NE neurons to CRF in females leads to greater cocaine seeking and more difficulty in maintaining abstinence. We will test these ideas by (i) determining the ability of beta adrenoceptor or CRFI receptor antagonists to attenuate cocaine seeking during early abstinence, (ii) identifying NE and CRF neurons that are Fos-activated during eariy cocaine abstinence, and (iii) determining if CRFI receptor antagonism within LC attenuates cocaine seeking during eariy abstinence. Findings here will inform Projects 1 and 4 about circuitry and neurotransmitters involved in drug seeking in their clinical subjects, and Project 2 about upstream circuits that may influence the peptide systems studied there. RELEVANCE (See instructions): This project will define the roles of specific brain systems in sex/gender differences in the initiation of abstinence from cocaine abuse. Results of these studies will lead to more effective treatments for addiction' in both males and females.

DESCRIPTION (provided by applicant): This application from the Medical University of South Carolina (MUSC) requests support for renewal of the Building Interdisciplinary Research Careers in Women's Health (BIRCWH) Program initially funded in 2007. The overall objective of MUSC's BIRCWH program is to attract translational scientists in the neuroscience arena to broaden interdisciplinary research related to women's health in South Carolina and throughout the U.S. Since its inception, the MUSC BIRCWH has supported 9 Scholars, including 4 PhDs, 4 MDs and 1 MD/PhD. All of the program graduates are Principal Investigators or Co-Investigators on research teams funded by extramural support. The program targets junior faculty who have an interest in developing a research careers addressing women's health and sex/gender issues in the neuroscience area. Scholars will remain in the program for a minimum of two and maximum of four years, depending on their level of training and experience at entry. We plan to have 5 Scholars in the program at any point in time, 4 supported by the BIRWCH program and 1 under-represented minority Scholar supported by an institutional commitment from the Dean of the College of Medicine. While each Scholar will have an individual career development plan, all will participate in core components, such as a seminar series focused on sex and gender issues in neuroscience research, MUSC's Sex and Gender Studies Research Day and training in responsible conduct of research, providing ample opportunity for interaction and the development of interdisciplinary collaborations. The substantial expertise in translational neuroscience at MUSC assures our ability to mentor individuals and contribute significantly to the understanding and treatment of women's health issues related to brain and behavior across the lifespan. Our 24 mentor-eligible faculty members from four health professional colleges (Medicine, Nursing, Health Professions, and Pharmacy) have broad skills in neurological and neuropsychiatric disorders, especially pertaining to neurodegenerative disorders, stroke, age-related dementia and cognitive decline, substance abuse, depression, and other mood and anxiety disorders. Their research interests are congruent with the special emphasis areas of Prevention and Treatment, and Biological and Behavioral Basis of Sex and Gender Differences, identified as high priority areas in the new BIRCWH RFA-OD-11-002.

PROJECT II: Sex Differences in Orexin and Oxytocin Mediation of Cocaine-seeking (See) Sex and gender differences have been reported in drug addiction for various drugs of abuse and across various stages of the addiction process. Moreover, cocaine seeking in females is closely linked to specific phases of the estrous cycle. Building on our previous discoveries of sex differences and hormonal influences in reinstatement to cocaine seeking, this project will examine two key neuropeptide substrates, orexin and oxytocin, that may underiie sex and estrous cycle-dependent differences in cocaine taking and reinstatement of cocaine seeking. Our broad hypothesis is that sex differences in cocaine seeking depend upon sexual dimorphisms in the orexin and oxytocin systems. The proposed studies will assess brain region specific changes in orexin and oxytocin, and test systemic and site directed receptor modulation of these peptide systems on cocaine seeking in males and females. The studies comprise a multifaceted neurobiological approach that complements the clinical SCOR projects that focus on gender differences and relapse in drug-dependent women and men, including the relationship of ovarian hormones to drug seeking. In addition, this project will integrate with the preclinical model of cocaine addiction proposed in Project 3 focused on the role of norepinephrine and corticotrophin-releasing factor (CRF) in males and females. RELEVANCE (See instructions): We will characterize fundamental sex and estrous cycle dependent differences in cocaine addiction and the role of two key neuropeptides, orexin and oxytocin, using an animal model closely linked with important clinical issues both conceptually (e.g., sex and ovarian cycle differences associated with cocaine addiction) and methodologically (e.g., analogous treatment with oxytocin). Providing relevant data on the neurobiology of cocaine addiction in males and females will guide future treatment approaches in human cocaine addicts.

The goal of the South Carolina Clinical and Translational Research Institute (SCTR) is to create a sustainable home at the Medical University of South Carolina (MUSC) to advance clinical and translational research as a distinct discipline and facilitate collaboration across multiple disciplines. The overall approach focuses on: (1) implementing important advances in biomedical science to create opportunities for discovery, (2) removing barriers to facilitate the linkage of knowledge, experience and expertise across disciplinary boundaries, (3) providing training and mentoring experiences to enhance the pipeline for clinical and translational researchers with diverse training and backgrounds, and (4) fostering community engagement with a rapidly growing statewide population that is underserved by many systems to improve their participation and health outcomes. MUSC has long-standing experience leading successful clinical and translational research efforts that span the state. It is the leading state institution in extramurally funded research activities and has a rich research training portfolio. SCTR was established in 2007 with the vision that it would be the agent of change in transforming the research culture at MUSC and statewide via strong relationships with academic and community-based affiliates. Great progress has already been made including the development of an institutional K12 Career Development Program in Clinical and Translational Research, implementation of a pilot project program that funded 29 projects in the first two competitive rounds, and establishment of a robust collaboration with the NIH-funded CTSA at Vanderbilt University for assistance in the SCTR Biomedical Informatics Program. Joining the national CTSA Consortium will accelerate progress by further facilitating (1) development and interoperability of biomedical informatics systems, (2) active exchange of best processes and best practices in evidence-based medicine and community engagement, (3) advancement of clinical and translational science as a discipline and career path; and (4) shared knowledge, experience and collective influence in setting regional and national research agendas and health policy designed to generate the transformative results envisioned by the NIH Roadmap. RELEVANCE (See instructions): SCTR will bring together scientists, clinicians and the lay community to address diseases that commonly impact the citizens of South Carolina. SCTR will coordinate resources and expertise statewide in efficient, innovative approaches to research. Through SCTR, a new generation of researchers will be trained to work across multiple disciplines in collaboration with community members so that scientific discovery is relevant and ranirilv tran.'slateri tn frnnt-linfi trfiatmfint .settinn.'s for maximum imnant nn health niitcnmes

DESCRIPTION (provided by applicant): This revised application from the Medical University of South Carolina (MUSC) requests support to establish a Mentored Clinical Scientists Development Program in Drug Abuse and Addiction (K12) at MUSC. The overall objective of the proposed program is to establish an intensive program of mentored clinical research training and career development activities that will promote Scholars' research independence in the area of drug abuse and addiction. In keeping with the mission of NIDA, a major aim of the proposed program is to attract and train clinical researchers to ensure that a diverse pool of highly trained scientists will be available to address the Nation's critical health care needs in te area of addictions. The proposed program, described in detail in the Program Plan section, consists of a unified core curriculum designed to address the following six objectives: (1) Increase addiction knowledge base; (2) Provide fundamental clinical research skills; (3) Enhance statistical skills; (4) Enhance research presentation skills; (5) Improve scientific writin skills; and (6) Provide professional development opportunities. A comprehensive evaluation utilizing formative and summative techniques, as well as recurrent formal and informal approaches for reviewing and evaluating both Scholar progress and program effectiveness will be conducted. Research training and career development opportunities in drug abuse and addictions are exceptionally strong at MUSC, as evidenced by ongoing, NIH-sponsored investigations targeting cocaine, prescription opioids, cannabis, methamphetamine, nicotine, and alcohol addiction. Investigations include studies of the biological mechanisms of addiction, behavioral laboratory studies, psychotherapeutic interventions, pharmacologic clinical trials, and neuroimaging studies. The substantial expertise in the area of clinical drug abuse and addiction research assures our ability to attract, train and prepare Scholars for independent research. The establishment of the NIDA K12 program at MUSC would meet an urgent need to extend the addictions research training potential to faculty-level trainees and allow us to work synergistically with existing pre-doctoral and post-doctoral training programs on campus to attract and promote career development in clinical research focused on addictions throughout the educational continuum.

ABSTRACT The MUSC Specialized Center of Research (SCOR) on sex/gender differences in addictive disorders and the relationship between stress and relapse has been highly productive for 15 years. In addition to coalescing a multidisciplinary group of investigators across different disciplines working closely together to explore sex and gender differences in addictions and the relationship between stress and drug use, the MUSC SCOR has provided a fertile training ground for new investigators and attracted senior investigators to apply their skills to sex- and gender-specific research. During the proposed renewal period, we will transition to a Specialized Center of Research Excellence (SCORE). We will continue to reach across campus and also extend our reach to nationwide, cross-SCORE collaborations and community-based initiatives focused on dissemination of research findings to improve health outcomes. The science within our research group also will grow with three tightly integrated research projects, new investigators and innovative technologies. To address critical public health needs, the proposed research projects will investigate sex differences in cannabis and opioid use disorders and directly inform addiction treatment development. The specific aims of this SCORE are to support and enhance translational scientific collaborations among the investigators conducting primary and pilot research projects, catalyze further growth of interdisciplinary sex- and gender-based research on the MUSC campus, expand foundational research training for Early Career Investigators dedicated to sex and gender-focused translational research, and develop strategic partnerships to enhance the translation and dissemination of SCORE findings and other relevant research to improve health outcomes.

ABSTRACT The MUSC SCORE Career Enhancement Core (CEC) will enhance and expand foundational research training for Early Stage Investigators dedicated to clinical and translational research on stress-related sex and gender differences via a mix of formal didactic modules, ?hands-on? experiential learning opportunities, and inter- program research offerings leveraging the rich portfolio of training programs and research expertise across the MUSC campus. The SCORE CEC will focus on facilitating the development of skills in multiple domains, including: (1) knowledge and skills to conduct research focused on sex and gender differences; (2) scientific knowledge and professional development; (3) fundamental research skills; (4) dissemination and presentation of research findings; and (5) scientific writing. The substantial expertise in stress-related research at MUSC ensures our ability to mentor individuals in early stages of their research careers to contribute significantly to the understanding and treatment of stress-related diseases and disorders. Further, the SCORE CEC will work synergistically with other training programs on the MUSC campus to attract and promote faculty development in research focused on sex and gender differences.

Abstract/Summary Approximately 25 million people experience daily chronic pain and many are prescribed opioids for pain management. Effective treatment options are limited. It is critically important to study new treatments with the potential to better manage pain. The Medical University of South Carolina (MUSC) Specialized Clinical Center (Hub) of the Early Phase Pain Investigation Clinical Network (EPPIC-Net) will provide a robust and readily accessible infrastructure for rapid implementation and performance of high-quality, comprehensive studies of novel treatments for patients with a wide variety of pain conditions. The MUSC-Hub will harness multidisciplinary clinical, research, statistical, and data management expertise to provide the scientific leadership and infrastructure required to design and conduct multi-site Phase-II clinical trials, biomarker validation studies, and deep phenotyping of patient populations as part of the EPPIC-Net with the overall goal of accelerating the development of new therapies for patients with acute and/or chronic pain. MUSC has numerous resources and extensive experience with pain assessment, outcomes tracking, and clinical trial protocol development. The leadership of the MUSC-Hub has extensive experience and expertise conducting high quality multi-site and single-site phase-II clinical trials for pain, clinical trial network participation and administration, research resource development and oversight, and collaborative team science background. The MUSC-Hub and spoke network has access to a vast number of patients with a wide variety of well- phenotyped pain conditions. Different spokes have expertise and experience with different pain populations, and the overall volume of patients with chronic and acute pain within the MUSC-Hub and spoke network is extensive, affording us the ability to quickly recruit and enroll participants in a wide variety of clinical and research settings across the state. Through this program, we aim to form multidisciplinary clinical trial teams with close connections to physicians who are clinical and research experts providing care to patients with pain in the fields of primary care, orthopedics, neurology, anesthesiology, rheumatology, surgery, pediatrics, obstetrics/gynecology, addiction sciences, pain psychology, pain rehabilitation and abdominal pain. We will develop a system to rapidly and flexibly engage a number of spokes and sub-spokes in phase-II clinical trials by leveraging resources of our CTSA and NIDA-CTN programs, demonstrate efficiency of the MUSC-Hub system by participating in at least 2 network trials per year, supporting recruitment of at least 100 well- phenotyped subjects with specific pain conditions into concurrent phase 2 trials, and contribute to EPPIC-Net by serving on steering committees, proposing trials, and providing expertise in clinical trial proposal development.

ABSTRACT Opioid use disorders (OUDs) are increasing at alarming rates in women. Stress and dysregulation in biologic stress response systems appear to play an important role in drug use, and the connection between stress and drug use may be particularly important for women. Alterations in the hypothalamic-pituitary-adrenal axis and noradrenergic system are important in pathophysiology of OUDs. There is evidence that alpha-2 adrenergic agonists, agents that decrease noradrenergic activity, may help to prevent relapse and decrease stress reactivity in individuals with OUD and prevent relapse to drug use. Of interest, alpha-2 adrenergic agents have demonstrated greater effect in decreasing stress-reactivity and craving in cocaine- and nicotine-dependent women as compared to men, but gender differences in the impact of alpha-2 adrenergic agents in individuals with OUD have not been systematically explored. In the proposed study, we will explore the impact of a new alpha-2 adrenergic agent, lofexidine, on stress and drug cues in a laboratory paradigm and on stress cues delivered in participants' natural environments over the course of a 4-week clinical trial in 208 opioid-dependent men and women (104 women, 104 men). We will use innovative mobile technology to measure response to stress cues repeatedly before, during, and after treatment to allow for assessment of craving, emotional state and stress-cue reactivity in the natural environment of women and men with OUD. We will also measure urine drug screens three times per week and assess medication compliance using an innovative video capture procedure. The proposed study has significant synergies with Projects 1 and 3, utilizing similar assessment and pharmacologic interventions, respectively. This project will provide important information about a novel treatment strategy which may expand personalized medicine strategies for individuals with OUD.

Project Abstract The current opioid use disorder (OUD) epidemic has resulted a rise in infections including not only HCV and HIV, but also invasive bacterial infections including Staphylococcus Aureus bacteremia, endocarditis, skin and soft tissue infections, and bone and joint infections. Persons admitted to hospitals with co-occurring OUD and related infections presents a critical time to intervene, both to improve infectious disease and opioid addiction outcomes. Most hospitals, particularly in under-resourced and rural areas, lack physicians trained in treatment of OUD, and standard care for patients even in busy academic urban hospitals typically consists of detoxification and referral to outpatient resources for follow-up treatment. This asks patients with severe OUD to tolerate withdrawal symptoms, risking premature exit from hospital, and relapse to opioid use after failure to connect with OUD treatment referrals. Results include long lengths of stay due to concern about relapse and non-adherence if patients leave the hospital, and readmissions after OUD relapse, lack of antibiotic adherence and reinfection, leading to both poor clinical outcome and high healthcare costs. Hospital settings that manage these infections are treating increasing numbers of people with untreated OUD. This provides an opportunity to engage patients in treatment of their OUD while managing their infections. Infectious Disease (ID) specialists and hospitalists are a critical and logical resource to build capacity and increase access to medication-assisted treatment (MAT). An injectable long-acting monthly formulation of buprenorphine (LAB) has a potential advantage for initiating OUD treatment within hospital settings and bridging to treatment after discharge to the community. We propose to test a new model of care (ID/LAB) in which opioid use disorder (OUD) is managed by ID specialists and hospitalists concurrent with management of the OUD-related infections, using long-acting injectable buprenorphine (LAB), followed by referral as soon as possible after hospital discharge to community resources for long term treatment of OUD. Adults admitted to a hospital for infections related to OUD (N = 200) will be identified at hospital admission and randomly assigned 1:1 to ID/LAB or treatment as usual (TAU), consisting of detoxification and referral to community-based treatment for OUD in parallel with treatment of the infectious disease. The primary outcome measure will be the proportion of patients enrolled in effective medication treatment for OUD (buprenorphine, methadone, or injection naltrexone) at 3 months (12 weeks) after randomization. Study sites will be three hospitals serving geographically diverse, mixed urban and rural communities across the Eastern U.S. With successful co- treatment of addiction and infectious diseases, OUD could be stabilized, while repeat infections are avoided, and risk of morbidity and mortality due to infection or overdose reduced.

PROJECT SUMMARY ? SCTR INSTITUTE Parent Award UL1-TR001450 Since 2009, the South Carolina Clinical and Translational Research Institute (SCTR) has transformed the research environment across South Carolina (SC) by creating a Learning Health System that supports high- quality clinical and translational research (CTR) and fosters collaboration and innovation. Headquartered at the Medical University of South Carolina (MUSC), SCTR has engaged stakeholders and created statewide partnerships to improve care and address social determinants of health across SC. However, greater than 75% of SC is rural, and all 46 counties contain areas designated as medically underserved, so health disparities remain an issue. Over the next five years, SCTR will strengthen its outreach to these medically underserved areas through collaboration with the Clemson University Health Extension Program and the MUSC Telehealth Center of Excellence. With a focus on implementation and dissemination as well as discovery, we will develop and demonstrate innovative technologies and outreach to improve the health of our stakeholders. We will build on prior successes and introduce innovative approaches to expand CTR across SC through the following aims: Aim 1. Extend and enhance high-quality, innovative, flexible curricula and training experiences for all levels of the CTR workforce, with particular emphasis on enhancing workforce heterogeneity and team science. Aim 2. Engage a diverse group of stakeholders as active partners in CTR to address health care priorities while enhancing the scientific knowledge base about collaboration and engagement. Aim 3. Promote greater inclusion across the full translational spectrum of research by engaging investigators from many disciplines and patient populations from diverse demographic backgrounds and geographic areas. Aim 4. Develop, demonstrate and disseminate innovative methods and processes to address barriers and accelerate the translation of research discoveries to improvements in human health that can be generalized to a variety of practice settings. Aim 5. Enhance the conduct of translational research through the development of secure and innovative informatics and digital health solutions, tools and methodologies that affect every aspect of CTR. SCTR?s vision is to be a major force in facilitating the translation of innovative science into practice to address the health priorities of the citizens of SC and beyond. To achieve this vision, SCTR?s mission is to catalyze the development of methods and technologies that lead to more efficient translation of biomedical discoveries into interventions that improve individual and public health. SCTR will serve as the statewide academic home for CTR, one that is well-integrated with SC?s healthcare systems and provides essential support for innovative, efficient, multidisciplinary research and research training. We will work within SCTR, with our partners across SC and with the CTSA Consortium to realize this vision.

ABSTRACT The MUSC Specialized Center of Research (SCOR) on sex/gender differences in addictive disorders and the relationship between stress and relapse has been highly productive for 15 years. In addition to coalescing a multidisciplinary group of investigators across different disciplines working closely together to explore sex and gender differences in addictions and the relationship between stress and drug use, the MUSC SCOR has provided a fertile training ground for new investigators and attracted senior investigators to apply their skills to sex- and gender-specific research. During the proposed renewal period, we will transition to a Specialized Center of Research Excellence (SCORE). We will continue to reach across campus and also extend our reach to nationwide, cross-SCORE collaborations and community-based initiatives focused on dissemination of research findings to improve health outcomes. The science within our research group also will grow with three tightly integrated research projects, new investigators and innovative technologies. To address critical public health needs, the proposed research projects will investigate sex differences in cannabis and opioid use disorders and directly inform addiction treatment development. The specific aims of this SCORE are to support and enhance translational scientific collaborations among the investigators conducting primary and pilot research projects, catalyze further growth of interdisciplinary sex- and gender-based research on the MUSC campus, expand foundational research training for Early Career Investigators dedicated to sex and gender-focused translational research, and develop strategic partnerships to enhance the translation and dissemination of SCORE findings and other relevant research to improve health outcomes.