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Molecular mechanisms of susceptibility to drug use

吸毒易感性的分子机制

基本信息

批准号：
10029887
负责人：
Stephanie Mary Groman
金额：
$ 4.86万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2021-01-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10029887
关键词：
Animals Behavior Behavioral Bioinformatics Biological Factors Biological Markers Calcium Signaling Chronic Computer Analysis Cytoskeleton Data Decision Analysis Decision Making Dependence Development Dissociation Drug Exposure Drug usage Environmental Risk Factor Exposure to Future Genetic Genetic Markers Genetic Models Genetic Predisposition to Disease Genetic Risk Goals Human Individual Learning Link Mediating Mediator of activation protein Mentors Mentorship Methamphetamine Methamphetamine dependence Mind Modeling Molecular Neurobiology Nucleus Accumbens Pathology Pharmaceutical Preparations Phenotype Predisposition Prevention Prevention strategy Principal Investigator Protein Sortings Proteins Proteomics Psychiatry Psychological reinforcement Rattus Research Research Personnel Research Proposals Resources Risk Risk Marker Role Ryanodine Receptor Calcium Release Channel SCA2 protein Self Administration Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Technology Tissues Training Training and Education Universities Variant Viral addiction base behavioral phenotyping differential expression drug of abuse early detection biomarkers early life stress education research experimental study improved insight interest motivated behavior neurotransmission novel novel therapeutic intervention protein expression sorting nexins trafficking

项目摘要

PROJECT SUMMARY / ABSTRACT The transition from drug use to abuse and, eventually, to dependence may be mediated by biological factors that are present prior to drug use. Although chronic exposure to drugs of abuse is known to disrupt many signaling pathways, little is known about the molecular mechanisms that mediate addiction susceptibility. There is considerable interest in identifying early biomarkers for addiction susceptibility to improve addiction prevention strategies. Most studies have been conducted in substance-dependent individuals where the dissociation between ‘susceptibility’ and ‘consequence’ is ambiguous. I have recently identified a behavioral phenotype in rats that reliably predicts future drug-taking behaviors and identified three proteins as potential mediators of addiction susceptibility: sorting nexin 1 (SNX1), ryanodine receptor 2 (RYR2), and ataxin 2-like (ATXN2L). These proteins are involved in intracellular trafficking, calcium signaling and cytoskeleton reorganization, and have been previously linked to addiction. Precisely how differences in expression of these proteins impact the signaling cascades underlying addiction susceptibility is not known. The overarching goal of this proposal is to determine the functional and molecular role of proteins that mediate addiction susceptibility and investigate how these factors are mechanistically linked to genetic and/or environmental components of risk for addiction. To accomplish this goal, the proposed research will combine sophisticated behavioral and computational assessments with viral, proteomic and bioinformatic approaches. In Aim 1 I will use an inducible and reversible viral construct to bi-directionally manipulate expression of SNX1, RYR2, and ATXN2L and also determine how changes in expression of SNX1, RYR2, and ATXN2L alter methamphetamine self-administration and protein signaling mechanisms. In Aim 2 I will determine if variation in the expression of SNX1, RYR2, and ATXN2L is altered in a model of genetic addiction susceptibility and is associated with increased addiction risk. In Aim 3 I will determine if variation in expression of SNX1, RYR2, and ATXN2L is altered in a model of environmental addiction susceptibility and is associated with increased addiction risk. Completion of these aims will generate new insights into the signaling mechanisms of addiction susceptibility that could identify early biological markers of risk for addiction and improve current strategies for addiction prevention. The Principal Investigator will receive mentorship and technical training in viral and proteomic technologies by experts in cell signaling and cellular mechanisms, and viral technologies in motivated behaviors. Yale University and the Department Psychiatry provide exceptional facilities and resources for completing the proposed experiments, as well as having an exceptional reputation and track record for mentoring and transitioning early-stage investigators in to independent investigators. The proposed training, education and research will provide the PI with the technical and professional training to become a successful, independent addiction investigator.

项目摘要/摘要