1990 — 1991 |
Blendy, Julie A |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
The Molecular Genetics of Ninac a Putative Myosin Kinase @ Johns Hopkins University |
0.904 |
2000 — 2004 |
Blendy, Julie A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Analysis of Drug Addiction @ University of Pennsylvania
Over time and with repeated administration many drugs of abuse will cause physical dependence that is expressed by a withdrawal syndrome when the drug is removed from the system. How drug effects lead to long lasting changes in the brain responsible for the addiction process is not well understood. Signaling via cAMP has been shown to be critical in the responses of a variety of drugs of abuse. The CREB (cAMP response element binding) protein has been identified as an important factor mediating a transcriptional response to elevated levels of cAMP and Ca2+. Using the techniques of gene targeting, mice have been generated which carry a mutation in the CREB gene. These mice exhibit a dramatically reduced withdrawal response following chronic morphine providing evidence that CREB is involved in physical opioid dependence. The overall goal of this research program is to evaluate the role of CREB in drug induced biochemical and behavioral changes in mice. In Specific Aim 1 we will analyze upstream components of the cAMP/PKA/CREB pathway in wild type and CREB deficient mice to characterize additional biochemical changes in cell signaling processes after deletion of the CREB protein that may be associated with behavioral actions of drugs of abuse. Abnormalities in the development of tolerance or rewarding properties may contribute to the reduction of naloxone precipitated withdrawal after chronic morphine in CREB mutant mice. In Specific Aim 2 we will evaluate the role of CREB in the development of tolerance and conditioned place preference to morphine using CREB mutant mice. A second member of the CREB/ATF family of transcription factors, namely CREM, is capable of substituting for many of the effects of CREB. In Specific Aim 3 we will characterize the role of CREM in the development of tolerance, dependence and withdrawal following chronic morphine. In Specific Aim 4, we will determine whether CREB or CREM has a more universal role in other forms of drug addiction by examining the induction and development of behavioral sensitization following cocaine in CREB and CREM mutant mice. The use of the above mouse models in the research program described here represent a definitive step to clarifying the molecular basis for the biochemical and behavioral changes involved in drug addiction. The complete understanding of these neurobiological mechanisms would open new perspectives for the future development of a more rational therapy for drug addiction.
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0.958 |
2004 — 2008 |
Blendy, Julie Ann |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
The Role of Creb and Opioid System in Nicotine Reward @ University of Pennsylvania
Animal models for nicotine dependence are critical for investigating molecular mechanisms associated with this addiction. The mouse is a tractable model that allows for dissection of these mechanisms at a level not afforded by human studies. In particular, genetically-altered mice can be used to analyze a variety of complex functions including those associated with addiction. A variety of drugs of abuse, such as morphine, cocaine and more recently nicotine, have been shown to activate the transcription factor CREB (CAMP response element binding protein) in the brain. We will utilize mice homozygous for a targeted mutation in CREB (CREBaD mutant mice) to test the hypothesis that CREB is a central signaling molecule required for the addictive properties of nicotine. We will test this central hypothesis in three specific aims. First, we will investigate if activation of the transcription factor CREB is critical for the manifestation of rewarding effects of nicotine using a conditioned place preference paradigm (CPP) for nicotine in wild type and CREBaD mutant mice. Next, we will determine if CREB is critical for the manifestation of aversive effects of nicotine withdrawal and/or the underlying mechanism responsible for the maintenance of nicotine reward. We will treat wild type and CREBaD mutant mice with nicotine and evaluate both physical (somatic signs) and psychological (conditioned place aversion) signs of withdrawal. Furthermore, the effects of a withdrawal period on subsequent rewarding properties of nicotine will also be evaluated. Lastly, we will establish if the rewarding properties of nicotine are mediated through the endogenous opioid system, and if this occurs in a CREB dependent manner. We will utilize the opioid receptor antagonist naloxone, as well as mv-opioid receptor knock-out mice to evaluate changes in CREB activation and behavioral responses in conditioned place preference following acute and chronic nicotine administration. Together, these studies will provide insights into the molecular mechanisms underlying nicotine reward as well as interactions between nicotine and the endogenous opioid system. The complete understanding of these mechanisms would open new perspectives for the successful treatment of nicotine addiction.
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0.958 |
2006 — 2010 |
Blendy, Julie Ann |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Genetic Analysis of Drug Addiction @ University of Pennsylvania
[unreadable] DESCRIPTION (provided by applicant): A key obstacle to successful treatment of drug addiction is relapse, which is frequently precipitated by exposure to stress. Relapse has been modeled in animal studies through reinstatement of responses to drug self-administration or conditioned place preference (CPP) by drug, cue or stress. We and others, have demonstrated that a variety of drugs of abuse, such as morphine, cocaine and more recently nicotine, can activate the transcription factor CREB (cAMP response element binding protein) and this activation is necessary for subsequent behavioral responses to these drugs. More recently, we have shown that CREB is required for stress-induced reinstatement of cocaine conditioned place preference (CPP), but not drug- induced reinstatement. The mouse is a tractable animal model that allows for investigation of relapse at the levels of behavior, neural circuitry and molecular mechanisms. In this proposal we will utilize mice homozygous for a targeted mutation in CREB (CREB alpha/delta mutant mice) to test the hypothesis that CREB is a central signaling molecule required for stress induced reinstatement of drug seeking behavior. We will test this central hypothesis in three specific aims. In Aim 1, we will investigate if activation of the transcription factor CREB is critical for the manifestation of reinstatement behavior following various stressors using a conditioned place preference paradigm (CPP), and determine the role of corticosterone and CRF in this response. As both stress and cocaine reinstate CPP in wild type mice, these circuits must converge on a final common pathway. In Aim 2, we will identify the pathways specific for stress versus drug induced reinstatement, as well as points of convergence. Moreover, retrograde tracing studies will enable us to identify the precise location of these neurons in key brain areas in the reinstatement circuitry. Lastly, in Aim 3 we will determine which genes in these key brain areas are direct CREB target genes. These studies will allow us to address the molecular mechanisms underlying drug relapse. This information will be valuable for the development of pharmacotherapeutic approaches that focus on regulation of CREB and its target genes. These studies may give rise to novel potential therapeutics that can ultimately be translated to the clinic for relapse prevention in humans [unreadable] [unreadable]
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1 |
2009 — 2013 |
Blendy, Julie Ann Lerman, Caryn [⬀] |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Administrative Core @ University of Pennsylvania
The Administrative Core of the CIRNA will: (1) monitor and evaluate the progress of the CIRNA, by coordinating the activities of the executive committee and the advisory board; (2) enhance interdisciplinary education of CIRNA trainees and faculty, by coordinating seminars and workshops, and by distributing articles of relevance; (3) enhance interdisciplinary communication among CIRNA investigators and enhance synergy across CIRNA components by coordinating formal and informal meetings among project/core investigators, and maintaining an intranet site and list-serve; (4) facilitate the developmental research program (with the Career Development Core), which solicits and funds promising developmental proposals by trainees and junior faculty; (5) support the CIRNA as a national resource, by providing access to results of CIRNA research and educational information, and by implementing a comprehensive data sharing policy; and (6) provide administrative and budgetary oversight for the CIRNA. Drs. Lerman and Blendy will co-lead the CIRNA and its Administrative Core, with responsibilities based on complementary expertise in preclinical research (Blendy) and clinical research (Lerman).
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1 |
2009 — 2010 |
Blendy, Julie Lerman, Caryn [⬀] Liu-Chen, Lee-Yuan (co-PI) [⬀] Zubieta, Jon-Kar (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Functional Characterization of Oprm1 A118g in Nicotine Dependence @ University of Pennsylvania
DESCRIPTION (provided by applicant): A substantial body of evidence implicates the endogenous opioid system, and the mu opioid receptor (MOR) in particular, in the reinforcing effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the mu opioid receptor gene (OPRM1 Asp40) is associated with the ability to quit smoking, as well as nicotine reward and withdrawal symptoms. However, the precise mechanism through which this SNP influences nicotine dependence remains unresolved. In this R21 application, we propose a translational cross-species approach to elucidate the functional significance of the OPRM1 Asp40 variant in the neurobiology of nicotine dependence. Toward this end, we have developed a knock-in mouse that possesses the mouse equivalent of the Asp40 in the Oprm1 gene (Asp38), and we provide compelling preliminary evidence for functional significance. Understanding whether this variant alters MOR binding in response to nicotine in mice and in human smokers will improve our understanding of genotype by nicotine interactions, and will provide a critical first step toward elucidating the neurobehavioral mechanisms through which this SNP alters smoking behavior. The proposed mice experiments will: 1) determine if the mouse Asp38 alters basal or nicotine-stimulated changes in MOR binding and signaling throughout the brain using [3H]carfentanil and autoradiography;and 2) evaluate the effect of the Asp38 variant on behavioral responses to nicotine using conditioned place preference and nicotine-primed re-instatement paradigms. The human experiment will use [11C]carfentanil PET imaging to assess the effects of intravenous (IV) nicotine versus saline (within-subject) on MOR binding potential in 24 chronic smokers genotyped prospectively and stratified by OPRM1 genotype. These experiments will establish a translational cross-species model for functional characterization of genetic variants, and will elucidate the neurobiology of nicotine dependence, a significant public health problem. PUBLIC HEALTH RELEVANCE: The proposed experiments in mice and humans will help us understand the mechanisms by which a specific gene variant (OPRM1 A118G) is associated with nicotine dependence.
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1 |
2009 — 2013 |
Blendy, Julie Ann |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Molecular and Behavioral Effects of Nicotine Deprivation @ University of Pennsylvania
Nicotine reward is an integral part of the addictive nature of nicotine, however, smoking and relapse to smoking are often motivated by the desire to alleviate negative affect and deficits in cognitive performance. Moreover, nicotine abstinence symptoms that promote smoking relapse are most evident in the first few days after quitting, suggesting this as a critical period to investigate neural mechanisms that may contribute to smoking relapse. To date, the underlying circuitry and mechanism(s) associated with alterations in emotional processing and learning and memory following nicotine deprivation have not been elucidated. Animal models for nicotine dependence are critical for investigating molecular mechanisms associated with this addiction. In particular, the mouse is a tractable model that allows for dissection of these mechanisms at a molecular and genetic level not afforded by human studies. Therefore, the overall goal of this project is to characterize novel phenotypes in mice to determine the effects of the early period of nicotine deprivation. Specifically, in Aim 1 we will determine the effects of nicotine deprivation on brain stimulation reward (BSR) and contextual learning and working memory. We hypothesize that chronic nicotine administration alters neural processes underlying affect and learning and memory such that when chronic exposure ceases, anhedonia and deficits in learning and memory will emerge. In order to increase our ability to develop novel therapeutic approaches to treat nicotine dependence, it is important to validate the use of our preclinical models and behavioral phenotypes with clinically effective medications. Therefore, in aim 2 we will evaluate the effects of systemic administration of varenicline (Chantix) on brain stimulation reward (BSR) and contextual learning and working memory following nicotine deprivation. As smokers often report stress relief as a motivating factor contributing to continued smoking behavior, we will investigate a role for stress factors (CRF) during the period of early nicotine deprivation. Thus, in aim 3, we will delineate the molecular mechanisms associated with nicotine deprivation through investigations of CRF by evaluating CRF receptor signaling mechanisms and a downstream target of this signaling cascade, CREB (cAMP response element binding protein). Together these studies will provide insights into the molecular mechanisms underlying nicotine deprivation. The complete understanding of these mechanisms would open new perspectives for the successful treatment of nicotine addiction.
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1 |
2011 — 2021 |
Blendy, Julie Ann |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Predoctoral Training Grant in Pharmacology @ University of Pennsylvania
DESCRIPTION (provided by applicant): This is an application for continuing support for an institutional predoctoral training program in Pharmacological Sciences currently in its 24th year. We request support for 12 predoctoral training positions for the next 5 years; this is the number of positions currently approved. The program is administered by the Graduate Group in Pharmacological Sciences (GGPS) and is the only program at the University of Pennsylvania that focuses on training students in fundamentals of pharmacology. The GGPS is made up of 76 faculty members from 20 Departments, 4 schools and 2 organizations; this diverse distribution along with a highly collaborative faculty creates an outstanding interdisciplinary research and training atmosphere for students. Currently there are 70 students in the program (60 TGE) with 50 students in thesis labs and 20 pre-thesis students. The training mission of the program is to provide a multifaceted flexible doctoral program that incorporates cutting edge research and a curriculum with 14 graduate Pharmacology courses that provides both depth and breadth in Pharmacology. The program is designed to prepare students as leaders in pharmacological sciences in academia, industry and government. Major areas of research, curriculum, and training include Neuropharmacology, Cell Signaling, Pharmacological Chemistry, Cancer Pharmacology, Cardiovascular Pharmacology, Pharmacogenetics, Environmental Toxicology, and Translational Medicine. Students take 4 required courses, 3 research rotations, 2 workshops and 3-4 additional electives in Pharmacology or related disciplines during the first 1.5 years in the program. Students take prelim exams in the form of an NIH grant proposal in the spring of year 2 followed by full time thesis research. Student training is enhanced by providing them multiple opportunities to present their research locally and nationally, student run journal clubs, seminars, and organizing and participating in an off-campus student symposium that focuses on graduate student research. Trainees receive guidance from the Academic Review Committee, academic advisors, thesis advisory committees, the GGPS chair, and PI of the training grant.
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1 |
2012 — 2016 |
Bartolomei, Marisa S. (co-PI) [⬀] Blendy, Julie Ann |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Transgenerational Effects of Drug-Exposure: Epigenetic and Behavioral Impact @ University of Pennsylvania
DESCRIPTION (provided by applicant): Drug addiction is a psychiatric disorder characterized by a transition from recreational to compulsive drug use that continues in spite of severe negative consequences. Despite attempts by individuals to quit, the desire or need to resume drug-taking can last for months or years. The persistence of addiction over time suggests that exposure to drugs results in long-term adaptations in the brain that likely involve alterations in transcription and genetic regulation. In addition to genetic factors, epigenetic mechanisms may also play a role in the maintenance of addictions not only throughout an individual's lifetime, but in his/her descendants. However, the potential impact of drug exposure across generations has not been characterized. To date, no comprehensive study has been undertaken to determine if exposure to drugs of abuse in the parental generation leads to alterations in behavioral or molecular phenotypes in subsequent generations. To address this question, we will examine the phenotypic consequences of two mechanistically different drugs (cocaine and morphine) in three inbred mouse strains (C57BL/6J, DBA/2J, A/J) as well as a multi-generation series of F1 hybrids. In addition to studying behavioral phenotypes across generations, we will characterize RNA expression, DNA methylation, and post-translational histone modifications as both the molecular signature and the mechanistic basis for heritable epigenetic changes. These studies will allow us to determine (1) whether any of 2 mechanistically different drugs of abuse results in transmission of addiction-related phenotypes through multiple generations after treatment, (2) whether these phenotypes are mediated by changes to the epigenome (DNA methylation, post-translational histone modifications, or RNAs), and (3) whether these phenotypes vary according to the sex of exposed parent in an imprinted or allele-specific manner. These experiments will inform future studies aimed at elucidating the mechanisms by which drugs of abuse lead to transgenerational phenotypes.
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0.958 |
2016 — 2020 |
Blendy, Julie Ann Kim, Sangwon F (co-PI) [⬀] Kim, Sangwon F (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Amp-Activated Protein Kinase (Ampk) and Nicotine Dependence @ University of Pennsylvania
? DESCRIPTION (provided by applicant): Smoking is the largest preventable cause of death and disease in the United States, with about 46 million U.S. adults currently smoking. Though there are medications approved by the FDA to treat nicotine addiction, they are minimally effective and at least 80% of those seeking treatment relapse within one year. Rewarding aspects of nicotine as well as aversive properties, such as those associated with abstinence, may act synergistically to direct the behavior of smokers toward tobacco consumption. Symptoms associated with nicotine withdrawal include increased anxiety and cognitive deficits. To date, few studies have investigated the molecular and cellular changes that occur during chronic exposure to nicotine and how these molecules are altered during withdrawal. Previously, we and others have established that the transcription factor CREB is a central mediator of addictive behaviors. We now made the discovery that one of the targets of CREB in the brain is the LKB1/AMPK pathway. AMP-activated kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that has a major role in the periphery in sensing cellular energy status and regulating fuel availability. Its role in the brain is virtually unknown. Preliminary data indicates that the AMPK pathway and its downstream targets are misregulated during nicotine exposure and withdrawal. The proposed mechanistic and translational studies will determine the functional role of this protein on nicotine reward behavior and withdrawal symptoms and will afford the development of novel or repurposed pharmacological treatments designed to promote smoking cessation.
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0.958 |
2017 — 2018 |
Blendy, Julie Ann |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Behavioral and Epigenetic Changes Following Adolescent Oxycodone Exposure @ University of Pennsylvania
Project Abstract It is estimated that 4.3 million people in the United States abuse prescription opioids (Center for Behavioral Health Statistics and Quality (CBHSQ) 2015) and that these are the second most abused illicit drugs by youths between the ages of 12 and 17. The long-term consequences of adolescent prescription opioid abuse on subsequent drug use in adulthood are unknown. Further, the underlying mechanism(s) associated with these behaviors are not known. Susceptibility of the adolescent brain to environmental insult is due, in part, to the massive neuronal reorganization and growth that occurs during this time. Recent studies have identified epigenetic regulation of several key genes as major contributors to adolescent neuronal development. Using tractable mouse models, we have evidence that adolescent oxycodone exposure augment morphine reward later in adulthood , and this is associated with changes in gene expression in the dopamine reward pathway. We will validate and extend these preliminary findings and identify potential underlying mechanisms by analyzing the epigenetic regulation of target gene expression as well as genome-wide histone post-translational modifications.
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0.958 |
2020 |
Blendy, Julie Ann Ehrlich, Michelle E (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neonatal Opioid Exposure and Withdrawal: Molecular and Behavioral Consequences @ University of Pennsylvania
Project Summary Opioid use among pregnant women is a growing public health concern in the United States. Infants exposed to opioids in utero are at high risk of exhibiting Neonatal Opioid Withdrawal Syndrome (NOWS), a combination of physical withdrawal symptoms including high pitched crying, sleeplessness, irritability, gastrointestinal distress, and in the worst cases, seizures. The complexity of this syndrome is amplified by a variety of clinical factors such as duration of maternal opioid exposure, maternal polypharmacy, environment, and genetics. The complexity of in utero opioid exposure and NOWS make it very difficult to investigate underlying molecular mechanisms that could ultimately inform early diagnosis and treatment. Therefore, we have developed a much needed mouse model of 3- trimester opioid exposure and withdrawal. Based on preliminary evidence, we hypothesize that microglia activation and immune mediators contribute to the severity of NOWS and a common SNP in the ?-opioid receptor modulates these effects. Using morphine as a prototypical opioid, we will exploit our model to test these hypotheses. First we will fully characterize the role of the innate immune system in NOWS and determine if regulation of neuroinflammation has therapeutic potential by pharmacological treatment with the anti- inflammatory drug, ibudilast. Second, as recent clinical findings suggest that genomic variation in the gene that encodes the ?-opioid receptor (Oprm1 A118G) may influence NOWS severity, we will use our mouse line that contains the equivalent Oprm1 A118G SNP to determine the impact of Oprm1 genetics on microglia activation and immune mediators. Using our model of 3-trimester opioid exposure and withdrawal we will use TRAP-Seq, a new technology for retrieving mRNAs within the ribosomal complex that are actively being translated, in our case in cells expressing m-opioid receptors, to interrogate the changing transcriptome following opioid exposure and withdrawal. This project is likely to have a sustained and powerful impact on the field because we will address mechanisms through which perinatal exposure to opiates results in NOWS, and how genetics and immune response contribute.
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0.958 |
2020 — 2021 |
Blendy, Julie A Childress, Anna Rose |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
T32 Translational Addiction Research Fellowship Program @ University of Pennsylvania
Addictions and the associated public health problems of HIV transmission, crime and violence, exact a severe toll on our nation, costing billions annually in health care, lost productivity, and incarceration. As there have been rapid advances in neuroscience and genetics in the past two decades, we need to speed the forward translation of this knowledge into more effective clinical treatments for the addictions. Conversely, for addiction treatments with some known efficacy, we can now apply new neuroscience and genetic tools in backward- translation -- e.g., finding why a treatment works well for some individuals, yet not at all for others. To help meet the need for skilled translational researchers, this application proposes continuation of a successful (17 total trainees; 13 in the current funding period) NIDA T32 Translational Addiction Research Fellowship at the University of Pennsylvania. The (pre- and postdoctoral) training program make explicit a long-standing translational tradition at Penn, integrating clinical and basic research strengths to create trainees, whether clinical or preclinical, Ph.D.s or M.D.s, who will accelerate addiction science in the next decade. The emphasis on translation is reflected at each level of the program - through the Co-PIs (clinical and basic, Drs. Childress and Pierce), the internal and external advisory board members, the formal didactics, the dual (clinical - preclinical) mentoring, and in the trainees' mentored research projects. The translational emphasis of the program is driven by the recognition that addictions are complex disorders, multi-determined by interaction of genetic vulnerabilities, exposure to drug, and a host of modulating (e.g., early trauma ,stress, cultural norms) influences. Trainees are thus offered state-of-the-art knowledge about these interacting determinants through a didactic series specific to the program, and through mentored projects that may range from molecular and genetic studies, to brain systems (neuroscience and neuroimaging), to clinical treatment trials, and drug policy. This wide range of choices is enabled by the long history of excellence in addiction research at the University, reflected in the several academic research Centers (Penn Center for Studies on Addiction; Translational Research Laboratories/CNB; Center for AIDS Research; Center for Integrated Nicotine Research (CIRNA), the Treatment Research Institute, and collaborative laboratories offering skilled, successful mentors to the Fellowship. Mentored research also takes place within several affiliated treatment settings (VA, Presby-Penn, community methadone clinics, and mobile HIV Prevention units), critical for translating new research findings into the real world?.
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0.958 |
2021 |
Blendy, Julie A Corder, Gregory (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mapping Opioid-Dependence State Transitions Across Structural, Functional, and Transcriptomic Topologies @ University of Pennsylvania
PROJECT SUMMARY Opioid addiction is a chronic, progressive disorder that fuels the current US epidemic of opioid overdose deaths. Over the years, a tremendous amount of research effort has been devoted to understanding the biological roles of opioid receptors and developing newer generations of synthetic opioids to treat pain and combat opioid addiction. However, given the advancement of contemporary and novel neuroscience technologies, we have the tools to think beyond mu-opioid receptors (MORs) to develop improved OUD therapeutics. This proposal aims to investigate the architecture and function of endogenous MOR-expressing neural circuits in the brain and to determine how these circuits maintain cellular dependence and drive brain-wide maladaptive plasticity across different stages of the OUD cycle. In four complementary aims, we will first map the shifting structural and functional connectivity of opioidergic networks using viral-genetic and tissue clearing methods to identify monosynaptic inputs to withdrawal-active MOR-expressing cells and axonal output projections, as a function of opioid exposure and abstinence. We will then integrate these input/output maps with cell-type information and gene expression changes within dependence networks using hyper-multiplexed 3D in situ hybridizations to generate the anatomic localization of hundreds of dependence-related genes, targeted to cell types and retro- labeled connections. Finally, to reveal how MOR-expressing cells within core regions are modulated during opioid exposure in real-time, we will use miniature head-mounted microscopes to image the population activity? at cellular resolution?across weeks of opioid exposure and withdrawal. Our models will provide formal summaries of activity, connectivity, and gene expression as they evolve with repetitive opioid exposure and withdrawal, and our datasets will be made publicly available as they are generated. To bridge these experimental measurements and provide a common framework for our analyses, we will adopt Network Control Theory to identify brain nodes that drive the transition between opioid dependence states to identify potential candidates that disproportionately drive each state.
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0.958 |