Gonzalo E. Torres - US grants

Re-uptake of neurotransmitters from the synaptic cleft is considered to a critical component in the termination of synaptic transmission. The dopamine transporter (DAT) plays a fundamental role (DAT) plays a fundamental role in maintaining the extracellular levels of dopamine thereby controlling the duration and the intensity of dopaminergic transmission. It is also a target site of anti-depressants and psychostimulants such as cocaine and amphetamine. Despite the importance of this molecule in the pathophysiology of affective disorders and drug abuse, little is known about the basic regulatory components associated with the molecular and cellular biology of this membrane protein. The studied proposed in this application are designed to identify novel intracellular proteins that interact with DAT and participate in transporter cellular regulatory mechanisms. In addition, the functional molecular determinants required for the assembly, regulated trafficking, and localization of DAT proteins will also be elucidate. Thus, the goals of this proposal is to delineate functional domains in the DAT protein, relative those domains to cellular regulatory mechanisms, and identify novel components that participate in the regulation of DAT expression and function. This information will provide a foundation for more in- depth studies that could lead to new opportunities for the development of therapeutic interventions used in the management of affective disorders and drug abuse.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Biogenic amine transporters have emerged as the indispensable molecules regulating monoamine transmission in the brain by controlling the duration and intensity of transmitter actions at specific molecular targets. Three distinct genes encode closely related plasma membrane transporter proteins: the dopamine transporter (DAT), the norepinephrine transporter (NET), and the serotonin transporter (SEPT). The primary role of these transporter proteins is to remove released transmitters from the synaptic cleft back into presynaptic terminals for subsequent vesicular storage and release. Deletion of the genes encoding biogenic amine transporters in mice results in profound neurochemical and behavioral changes, thereby, illustrating the impact of these transporters in controlling presynaptic monoamine homeostasis. A wide spectrum of neurological and psychiatric disorders, including drug abuse, affective disorders, and Parkinson's disease is thought to involve monoamine transmission and monoamine transporters. Indeed, it has been well established that biogenic amine transporters are the biological targets for potent psychostimulants such as cocaine, amphetamine, and (+)-3,4-methylenedioxymethamphetamine (MDMA or ecstasy) as well as therapeutic agents used to treat mental disorders including depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and eating disorders. Recently, results from our and other laboratories suggest that monoamine transporters are highly regulated proteins and indicate a more complicated degree of organization for these transporters than previously anticipated. Findings include the elucidation of the oligomeric nature of DAT, the identification of domains involved in assembly and trafficking, and the identification and preliminary characterization of interacting proteins that regulate the targeting, trafficking, and function of monoamine transporters. Based on these results, I hypothesize that monoamine transporters exist as highly regulated macromolecular protein complexes in neurons. Thus, the overall goal of this research proposal is to provide a clearer understanding of the cellular regulatory mechanisms associated with monoamine transporters by identifying interacting proteins and establishing the role of such protein-protein interactions in transporter function. The following specific aims are proposed: Aim I: To determine the total complement/network of protein-protein interactions involved in biogenic amine transporter complexes in vivo using proteomic approaches. Aim II: To elucidate the physiological role of PICK1 and Hic-5 in the regulation of DAT function using genetic approaches. Aim IlI: To examine biochemically and functionally if putative interacting proteins identified previously in a yeast two-hybrid screen are real DAT interacting proteins. These studies should provide unprecedented insights into the regulation of monoamine transporters in brain and novel molecular targets for therapeutic approaches. This research proposal has also been designed to further develop the scientific career of the P.I. in preparation for an independent faculty position by acquiring expertise in proteomic and genetic approaches from internationally recognized scientists to better address the role of biogenic amine transporters in normal and abnormal brain function. [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Biogenic amine transporters have emerged as the indispensable molecules regulating monoamine transmission in the brain by controlling the duration and intensity of transmitter actions at specific molecular targets. Three distinct genes encode closely related plasma membrane transporter proteins: the dopamine transporter (DAT), the norepinephrine transporter (NET), and the serotonin transporter (SEPT). The primary role of these transporter proteins is to remove released transmitters from the synaptic cleft back into presynaptic terminals for subsequent vesicular storage and release. Deletion of the genes encoding biogenic amine transporters in mice results in profound neurochemical and behavioral changes, thereby, illustrating the impact of these transporters in controlling presynaptic monoamine homeostasis. A wide spectrum of neurological and psychiatric disorders, including drug abuse, affective disorders, and Parkinson's disease is thought to involve monoamine transmission and monoamine transporters. Indeed, it has been well established that biogenic amine transporters are the biological targets for potent psychostimulants such as cocaine, amphetamine, and (+)-3,4-methylenedioxymethamphetamine (MDMA or ecstasy) as well as therapeutic agents used to treat mental disorders including depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and eating disorders. Recently, results from our and other laboratories suggest that monoamine transporters are highly regulated proteins and indicate a more complicated degree of organization for these transporters than previously anticipated. Findings include the elucidation of the oligomeric nature of DAT, the identification of domains involved in assembly and trafficking, and the identification and preliminary characterization of interacting proteins that regulate the targeting, trafficking, and function of monoamine transporters. Based on these results, I hypothesize that monoamine transporters exist as highly regulated macromolecular protein complexes in neurons. Thus, the overall goal of this research proposal is to provide a clearer understanding of the cellular regulatory mechanisms associated with monoamine transporters by identifying interacting proteins and establishing the role of such protein-protein interactions in transporter function. The following specific aims are proposed: Aim I: To determine the total complement/network of protein-protein interactions involved in biogenic amine transporter complexes in vivo using proteomic approaches. Aim II: To elucidate the physiological role of PICK1 and Hic-5 in the regulation of DAT function using genetic approaches. Aim IlI: To examine biochemically and functionally if putative interacting proteins identified previously in a yeast two-hybrid screen are real DAT interacting proteins. These studies should provide unprecedented insights into the regulation of monoamine transporters in brain and novel molecular targets for therapeutic approaches. This research proposal has also been designed to further develop the scientific career of the P.I. in preparation for an independent faculty position by acquiring expertise in proteomic and genetic approaches from internationally recognized scientists to better address the role of biogenic amine transporters in normal and abnormal brain function. [unreadable] [unreadable] [unreadable] [unreadable]

Neurons communicate to other cells through the actions of neurotransmitter molecules acting on receptor proteins. Transmitters are stored in synaptic vesicles and released via a calcium-dependent mechanism involving several protein-interactions and the fusion of synaptic vesicles with the plasma membrane. Synaptic vesicles are then retrieved from the plasma membrane and quickly refilled with transmitter molecules to maintain an efficient cycle of neurotransmission. While the molecular details of transmitter release and vesicle retrieval have been the subject of intense investigation, almost no information is available regarding the molecular basis of the vesicular refilling process. Dr. Torres' research program has focused on the functional regulation of the dopamine transporter (DAT). Preliminary data from the Dr. Torres' laboratory demonstrate a direct interaction between DAT and the synaptic proteins SNAP-25 and synaptogyrin-3. SNAP-25 is one of the SNARE proteins involved in synaptic vesicle docking and fusion whereas synaptogyrin-3 is a transmembrane synaptic vesicle protein. The association of DAT with a SNARE protein and a synaptic vesicle protein could provide the molecular basis for a physical and functional coupling between the plasma membrane DA re-uptake system and synaptic vesicles for subsequent vesicular uptake. Thus, a physical and functional coupling between DAT and synaptic vesicles would ensure a rapid and efficient mechanism for re-filling vesicles with DA after neurotransmitter release. Therefore, to explore this hypothesis, Dr. Torres will examine the physiological significance of DAT protein-protein interactions with the synaptic proteins SNAP-25 and synaptogyrin-3. The following aims will be pursued: Aim 1 will examine the molecular determinants involved in DAT interactions with SNAP-25 and synaptogyrin-3 and the specificity of these interactions. Aim 2 will examine the functional consequences of disrupting these interactions on DAT function and vesicular DA storage. Aim 3 will test the hypothesis that manipulations that alter vesicular DA storage also have an effect on DAT function and DAT interactions with SNAP-25 and synaptogyrin-3. Aim 4 will test the hypothesis that DAT interacts physically and functionally with synaptic vesicles.

This research will not only increase the understanding of synaptic transmission and molecular mechanisms associated with synaptic vesicular refilling, but will also provide undergraduate and graduate students with research opportunities in neuroscience. Dr. Torres is an Assistant Professor in the Department of Neurobiology at the University of Pittsburgh since July 1, 2004. During the past year, he has been nominated to the Minority Education Training Professional Advancement Committee (METPAC) from the Society for Neuroscience and to the Committee on Minorities from the American Society of Pharmacology and Experimental Therapeutics (ASPET), where he is currently the Chair of the committee. In addition, Dr. Torres oversees minority recruitment to the Center for Neuroscience graduate program at the University of Pittsburgh. It is the aspiration and interest Dr. Torres to use these positions and connections to actively recruit and lead young, aspiring, and especially minority researchers to be involved in the proposed work.

[unreadable] DESCRIPTION (provided by applicant): Dopamine (DA) is an essential neurotransmitter and plays a major role in the rewarding effects of psychostimulants, including cocaine and amphetamine. A primary component of DA neurotransmission that determines the lifetime of DA at synapses is the re-uptake of the transmitter back into nerve terminals by the DA transporter (DAT). Importantly, many psychostimulants produce their reinforcing effects primarily by altering the function of DAT. Therefore, it becomes necessary to understand the regulatory mechanisms associated with DAT function in order to assess their role in mediating the effects of pyschostimulants. Recently, we and others have identified several DAT protein interactions, suggesting that synaptic distribution, functional properties, and molecular actions of psychostimulants at DAT can be regulated via associated proteins. Specifically, we identified the synaptic vesicle protein synaptogyrin-3 (SG3) as a DAT interacting protein using a proteomic approach. These studies have produced ample data demonstrating a physical and functional interaction between the amino terminus of DAT (DATN) and SG3 in vitro. We hypothesize that the DAT/SG3 interaction facilitates synaptic vesicle docking at the plasma membrane near DAT to provide efficient loading of the vesicles with extracellular dopamine during the reuptake process. Importantly, this interaction might mediate some actions of psychostimulants. To date, the impact of protein-protein interactions on DA homeostasis or the effects of psychostimulants has not been examined in vivo. In order to provide a mode of investigation for the role of DAT protein-protein interactions in the regulation of DA homeostasis in vivo, we propose an explorative approach that will combine two contemporary methodologies. Fast scan cyclic voltammetry (FSCV), has been used by many in conjunction with electrical stimulation and/or pharmacological manipulation to obtain information about temporal changes and concentration of catecholamines in the central nervous system. The second contemporary technique we will employ involves the use of TAT-conjugated interfering peptides to effectively deliver the DAT binding domain of SG3 to the brain. Our group has begun to use these two approaches together with the goal of discerning whether disrupting the DAT/SG3 interaction impacts DA neurotransmission. Indeed, preliminary data suggests that administration of the DAT-N fused to TAT disrupts the interaction between SG3 and DAT and has profound adverse consequences on in vivo striatal DA neurotransmission. We propose to examine systematically the functional consequences of disrupting the DAT/SG3 protein-protein interaction on DA neurotransmission and to evaluate the effects of this interaction on psychostimulant response. The studies described in this proposal are expected to support the goal of developing novel therapies for drug addiction. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Dopamine (DA) transmission is involved in important brain functions including locomotor control, neuroendocrine secretion, cognition, emotion, and reward. Dopaminergic signaling is terminated primarily by the re-uptake of the transmitter via a plasma membrane DA transporter (DAT). This protein is also the main target of widely abused psychostimulants, such as cocaine and amphetamine. Recently, our group and others have identified several proteins that interact with DAT and play important roles in targeting, trafficking, and functional regulation of the transporter. Using the yeast mating-based split ubiquitin system, we have now identified the synaptic vesicle protein synaptogyrin-3 (SG3) as such a DAT interacting protein. We have gathered preliminary data suggesting a physical and functional interaction between DAT and SG3. Based on these observations, our central hypothesis is that a physical and functional interaction between SG3 and DAT influences transporter function and ultimately DA homeostasis. This may be due to a link between the plasma membrane DAT-mediated uptake and the vesicular DA storage system, or alternatively, through regulation of DAT targeting, recycling, and/or intrinsic transporter activity. In this application, a combination of biochemical, molecular, and functional approaches in vitro and in vivo will be used with cells in culture, synaptosomal preparations, purified synaptic vesicles, and whole animals to generate a detailed structural, functional, and subcellular description of the DAT/SG3 interaction. Specifically, we will identify the protein residues involved in the DAT/SG3 interaction and examine the specificity of this interaction (Aim 1); investigate the impact of SG3 on DAT function (Aim 2); examine the regulation of the DAT/SG3 interaction (Aim 3); and determine the subcellular location for the DAT/SG3 interaction (Aim 4). The long-term goal of our research program is to understand the mechanisms involved in the regulation of DA homeostasis by DAT and how these mechanisms are altered by psychostimulants. The discovery of novel DAT interacting proteins may suggest novel mechanisms associated with the activity of the transporter, and as a consequence, these mechanisms will have an important impact in the regulation of DA homeostasis. Public Health Statement: Findings from these studies are expected to aid in the advancements of new strategies for intervention in DA-related disorders including drug addiction. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Excitatory amino acid transporters (EAATs) in the CNS maintain extracellular glutamate concentrations below excitotoxic levels and contribute to the clearance of glutamate released during neurotransmission. Over the previous funding period our laboratory took advantage of a highly functional cysteineless version of EAAT1, to identify the structural features required for substrate transport and ion permeation using cysteine substitutions together with sulfhydryl modifying reagents. In this competing renewal application we plan to assess proximity of different residues during the transport cycle using introduced cysteine pairs and crosslinking reagents. Studies will continue to emphasize kinetic, biochemical, pharmacological and electrophysiological analyses of EAAT function. In a second aim these approaches will be combined with experiments using computational methods to model the conformational dynamics of glutamate transporters. Gaussian network modeling (GNM) and molecular dynamic (MD) simulations are techniques ideally suited for the study of large, multifunctional structures such as ion channels and neurotransmitter transporters. To date, methods that treat such multimeric proteins have been restricted to atomic interactions or limited, sub- nanosecond time ranges, which are too localized or fast compared to the phenomena that are observable in our experiments. The use of these two complementary methods provide a robust way of identifying critical interactions, which then can be tested by structure-function experiments designed to alter the structure and mobility of the domain of interest. A third aim will explore the mechanism of action of a neuroprotective compound purified from a spider venom, which appears to enhance transport activity by altering a less studied transition step in the transport cycle, the reorientation of the unoccupied carrier to the outside. This compound, which acts selectively on the major glial carrier EAAT2, increases glutamate influx but not efflux, and provides proof of principle for the development of allosteric activators of EAATs with therapeutic potential. The importance of understanding the structure, function, and dynamics of excitatory amino acid transporters is underscored by clinical and experimental studies, which have implicated increases in extracellular glutamate concentration in degenerative disorders such as ALS, Huntington's disease, ischemia-induced neurotoxicity, and Alzheimer's dementia.

DESCRIPTION (provided by applicant): Despite many years of discussion, research, and efforts to promote change, a great disparity remains between the presence of black, Hispanic, Native American, and other underrepresented minority (URM) faculty at US research universities and their representation in the American population. This reality is no less true in te neurosciences than in other disciplines. Moreover, URMs who do achieve faculty status appear to achieve traditional measures of success at a lower rate than do their majority counterparts. Although data on publications and funding rates appear to be lacking, there is a striking absence of URMs in visible positions of prominence as full professors or chairs at research universities and as symposia speakers, journal editors, or societal officers. We believe that these two problems are related - that if those URMs who are faculty become more successful in regard to those measures, this in turn will stimulate an influx of other URMs into faculty ranks. Our evaluation of available programs in the United States strongly indicates that there are limited opportunities to adequately assist early career URM faculty in overcoming these difficulties, and it is this problem that we seek to address through the establishment of a nationa Early Career Institute (ECI) to promote the advancement of junior faculty members in the neurosciences at research universities. Defining success for such faculty in terms of quality and quantity of manuscripts published and research grant proposals submitted, scored, and funded, we propose to establish an ECI based on the following hypothesis: The success of early career URM faculty members in neuroscience can be increased substantially by an intensive individualized educational program focused on (1) exposure to cutting edge research in basic neuroscience, (2) increased background on the neurobiology of disease, (3) instruction in professional skills and the responsible conduct of research (RCR), (4) development of an expanded network, and (5) frequent mentoring by established faculty. To test this hypothesis we wish to establish a national Early Career Institute (ECI) to advance the development of URM faculty. We will begin by identifying 10 URM faculty members in the neuroscience each year who are early in their career and have great promise for success. We will then develop individualized career development programs for each participant selected and together the participant and mentoring team will develop a career development plan. To facilitate that plan we will establish a one- year educational program consisting of (a) workshops, (b) mentored attendance at professional scientific meetings, (c) assistance in the expansion of their network, and (d) a listserv to promote communication among the participants. The impact of our efforts will be carefully evaluated and the results disseminated at meetings and in published articles. We believe that this approach will have a significant impact on the success of early career URM faculty in the neurosciences and will also serve as a model for programs in many other areas of academia.

DESCRIPTION (provided by applicant): The dopamine transporter (DAT) plays a crucial role in the regulation of brain dopamine (DA) homeostasis. Through re-uptake of DA, DAT serves two important functions: the termination of synaptic transmission at dopaminergic terminals, and the replenishment of vesicular DA pools. In addition to uptake or direct transport, DAT can also function to release DA. This process, which is referred to as reverse transport or efflux, is the mechanism used by potent and highly addictive psychostimulants, such as amphetamine and its analogues, to increase extracellular DA levels in motivational and reward areas of the brain. It has long being recognized that DA neurons release DA through exocytotic and non-exocytotic processes. However, the exact mechanism by which physiological signals or psychostimulants, such as amphetamine, induce DA release through DAT still remains a complex and not completely understood area of research. Thus, examining the basic mechanism(s) that affect reverse transport through DAT is critical for both understanding fundamental aspects of DA regulation and clinical intervention in DA-related brain disorders associated with the therapeutic use and abuse of psychostimulants. The long-term goal of our research program is to identify and characterize signaling mechanisms that control DA release through DAT, and elucidate the molecular actions of psychostimulants. This application is based on our recent discovery that the beta upsilon subunit of G proteins (Gbetagamma) binds DAT and regulates transporter activity. This effect was demonstrated in cultured cells, brain synaptosomes, and in vivo. More importantly, activation of Gbetagamma promotes DAT-mediated DA efflux, whereas inhibition of Gbetagamma attenuates amphetamine-elicited DA efflux in cultured cells. Finally, activation of Gbetagamma enhances whereas inhibition of Gbetagamma reduces amphetamine-evoked locomotor activity in vivo. Based on these preliminary data, the central hypothesis of this proposal is that the interaction between DAT and beta upsilon subunits promotes DA release through DAT and is involved in the actions of amphetamine. In this proposal we will i) identify the Gbetagamma interaction site(s) in DAT and their role in transporter regulation, ii) test the hypothesis that Gbetagamma is involved in DAT-mediated DA efflux, and iii) test the hypothesis that Gbetagamma is involved in amphetamine's actions in vivo. The successful completion of the studies proposed here will provide a detailed characterization of the DAT-Gbetagamma interaction and a clear understanding of its contribution to DAT reverse transport. The fact that amphetamine induces DAT reversal suggests that DA can also be released through DAT under physiological conditions. Therefore, our proposed studies will define not only the role that Gbetagamma subunits play in the addictive properties of amphetamine, but also the contribution of Gbetagamma subunits to DA homeostasis as we grow our current understanding of the molecular details underlying physiological DAT reverse transport. The long-term goal of our research program is to identify novel therapeutic targets that can be used in the treatment of neuropsychiatric disorders, including drug addiction.

The central goal of this study is to investigate the functional and physical interplay between the dopamine (DA) D2 autoreceptor (D2R) and the dopamine transporter (DAT) and the role of this interplay in the regulation of DA neurotransmission. DA neurons are functionally heterogeneous with spatially separated somatodendritic and axonal projections initiating in two neighboring brain structures; ventral tegmental area (VTA) and substantia nigra (SN). Aberrations in DA neurotransmission are implicated in neuropsychiatric disorders; including schizophrenia, attention deficit/hyperactivity disorder (ADHD), drug addiction, and Parkinson's disease. Critical mechanisms in the regulation of DA availability at the synapse include the activation of D2 autoreceptors and DA uptake via DAT. Traditionally, these two mechanisms ? D2R and DAT- have been studied individually; however, exciting new evidence from in vitro experiments suggests that D2 autoreceptor and DAT interact physically and possibly functionally. Published data and our own preliminary findings support the hypothesis that D2 autoreceptor and DAT exist as a macromolecular complex and that D2 autoreceptor activation regulates DAT activity and trafficking in DA neurons through a GIRK-mediated mechanism. To address this hypothesis we will use a multidisciplinary approach combining molecular, biochemical, electrophysiological, and optic approaches in cultured DA neurons and brain slices containing somatodendritic regions of VTA, SNc and their projection areas (dorsal striatum and nucleus accumbens) where both DAT and D2R are co- expressed. In aim 1, we will use genetic, electrophysiological and optic tools to examine functionally whether D2R activation increases DAT activity and trafficking through a mechanism involving GIRK-mediated hyperpolarizarion of the cell membrane. In aim 2, we will use molecular, biochemical, and optic tools to examine the contribution of the D2R-DAT physical interaction to the D2R-mediated regulation of DAT activity and trafficking. We will compare and contrast findings obtained from SN and VTA, projections areas in the dorsal striatum vs nucleus accumbens, as well as samples from male and female animals. Given the role of D2R and DAT as therapeutic targets for DA-related conditions, the successful completion of this work will reveal the physiological significance of the interplay between presynaptic D2 receptor and DAT. The result of this work will have wide-ranging significance, as it will reveal a unique mechanism for the FDA approved D2R agonists' and DAT antagonists' regulation of dopamine neurotransmission.   

Project abstract We propose to establish a new national training program in response to the NIGMS initiative, ?Innovative Program to Enhance Research Training? (IPERT), that is designed to increase the size of a highly skilled, successful, and diverse behavioral and biomedical workforce. Our intension is to accomplish this by instructing researchers at academic institutions, research institutes, scientific societies, and private industry in the best professional skills, including research ethics, and in the ways by those skills can be effectively transmit to trainees at their home institutions or professional societies. It is our believe that such instruction is necessary to maximize the success and scientific integrity of individuals engaged in behavioral and biomedical research. This is because, whereas most post-baccalaureate research training programs provide their trainees with a strong background in a scientific discipline and relevant laboratory skills, much more is needed to maximize the likelihood these individuals will advance in their careers and do so with a high level of integrity. As successful research scientists they will require a wide variety of additional skills, including the ability to develop a rigorous research program that generates reproducible data; fund that research through successful grant proposals; obtain and succeed in employment; communicate effectively through oral presentations, posters, research manuscripts, and informal networking; manage time, stress, and conflict; become effective lab managers, educators, and mentors; and exhibit social responsibility, including taking the time to effectively communicate with lay communities. In a great many cases the development of such skills will require explicit instruction. We believe that such instruction should be provided by individuals actively involved in research and should occur both within core academic courses and as part of workshops on these skills that include a discussion of their ethical dimensions, rather than via separate courses in research ethics. Our team is made up of a diverse group of individuals who ? separately and collectively ? have been involved for many years in instructing others in these skills both directly and through ?train-the-trainer? workshops. We now propose to expand those previous efforts substantially by developing improved materials, including cases for discussion and other handouts, slide decks, and videos; addressing a much broader range of topics than in the past; increasing the relevance of our training programs for a diverse workforce that includes ethnic minorities and individuals with disabilities; delivering those materials via larger and more diverse workshops and websites; and producing a training manual. We will also help workshop participants develop ways to establish a climate of inclusion at their home institutions. The impact of our workshops, designed for a minimum of 50 trainers each year, will be carefully assessed by a professional evaluator who will collect and report data on the participants? evaluation of our workshops; the impact the workshops have on participants? subsequent instructional activities; and the effectiveness of the participants in imparting what they have learned to their trainees, who may include college students, graduate students, postdoctoral fellows, laboratory staff, faculty, and/or staff scientists.

ABSTRACT Despite many years of discussion, research, and efforts to promote change, a great disparity remains between the presence of African American, Hispanic, Native American, People with Disabilities, and other underrepresented minority (URM) faculty at US research universities and their representation in the US population. This reality is no less true in the neurosciences than in other disciplines. Moreover, URMs who do achieve faculty status appear to achieve traditional measures of success at a lower rate than do their majority counterparts. Although data on publications and funding rates appear to be lacking, there is a striking absence of URMs in visible positions of prominence as full professors or chairs at universities and as symposia speakers, journal editors, or societal officers. We believe that these two problems are related ? that if those URMs who are faculty become more successful in regard to those measures, this in turn will stimulate an influx of other URMs into faculty ranks. Our evaluation of available programs in the US indicates that there are limited opportunities to adequately assist early career URM faculty in overcoming these difficulties, and it is this problem that we seek to address through the Center for Underrepresented Research in Addiction (CURA) to promote the advancement of junior faculty members in drug addiction research at research universities. Defining success for such faculty in terms of quality and quantity of manuscripts, grants submitted, and funded, visibility at the national level, mentoring of others by the participants, and promotion, we propose to establish a program based on the following hypothesis: The success of early career URM faculty in drug addiction research can be increased substantially by an intensive individualized educational program focused on (1) and individualized career development plan and the identification of a team of relevant mentors (2) strong instruction in professional skills and the responsible conduct of research (RCR), (3) individualized and frequent mentoring by senior established faculty (4) development of an expanded network and peer-mentoring, and (5) the promotion and enhancement of the career of URM faculty at their own institutions. To test this hypothesis, we will develop the CURA program to advance the career of URM faculty. We will recruit 10 early career URM faculty in drug addiction research each year for five years who have great promise for success. We will then develop career development programs for each participant and together the participant and mentoring team will develop a career development plan. To facilitate that plan we will establish a one-year educational program consisting of (a) workshops, (b) strong mentoring, (c) attendance at professional scientific meetings, (d) assistance in the expansion of their network, and (e) mechanisms to promote communication and peer-mentoring among the participants. The impact of our efforts will be evaluated and the results disseminated at meetings and in publications. We believe that this approach will have a significant impact on the success of early career URM faculty in the neurosciences and will serve as a model for programs in other areas of academia.

ABSTRACT Despite many years of discussion, research, and efforts to promote change, a great disparity remains between the presence of African American, Hispanic, Native American, People with Disabilities, and other underrepresented minority (URM) faculty at US research universities and their representation in the US population. This reality is no less true in the neurosciences than in other disciplines. Moreover, URMs who do achieve faculty status appear to achieve traditional measures of success at a lower rate than do their majority counterparts. Although data on publications and funding rates appear to be lacking, there is a striking absence of URMs in visible positions of prominence as full professors or chairs at universities and as symposia speakers, journal editors, or societal officers. We believe that these two problems are related ? that if those URMs who are faculty become more successful in regard to those measures, this in turn will stimulate an influx of other URMs into faculty ranks. Our evaluation of available programs in the US indicates that there are limited opportunities to adequately assist early career URM faculty in overcoming these difficulties, and it is this problem that we seek to address through the Mentoring Institute for Neuroscience Diversity Scholars (MINDS) to promote the advancement of junior faculty members in the neurosciences at research universities. Defining success for such faculty in terms of quality and quantity of manuscripts, grants submitted, and funded, visibility at the national level, mentoring of others by the participants, and promotion, we propose to establish a program based on the following hypothesis: The success of early career URM faculty in neuroscience can be increased substantially by an intensive individualized educational program focused on (1) and individualized career development plan and the identification of a team of relevant mentors (2) strong instruction in professional skills and the responsible conduct of research (RCR), (3) individualized and frequent mentoring by senior established faculty (4) development of an expanded network and peer-mentoring, and (5) the promotion and enhancement of the career of URM faculty at their own institutions. To test this hypothesis we will continue the MINDS program to advance the development of URM faculty. We will recruit 10 early career URM faculty in neuroscience each year who have great promise for success. We will then develop career development programs for each participant and together the participant and mentoring team will develop a career development plan. To facilitate that plan we will establish a two-year educational program consisting of (a) workshops, (b) strong mentoring, (c) attendance at professional scientific meetings, (d) assistance in the expansion of their network, and (e) mechanisms to promote communication and peer-mentoring among the participants. The impact of our efforts will be evaluated and the results disseminated at meetings and in publications. We believe that this approach will have a significant impact on the success of early career URM faculty in the neurosciences and will serve as a model for programs in other areas of academia.