Molecular Mechanisms of Susceptibility to Drug Use.

药物使用敏感性的分子机制。

基本信息

批准号：
10936772
负责人：
Stephanie Mary Groman
金额：
$ 14.66万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-04 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10936772
关键词：
Animals Behavior Behavioral Bioinformatics Biological Factors Biological Markers Breeding Calcium Signaling Chronic Computer Analysis Cytoskeletal Modeling Data Decision Analysis Decision Making Dependence Development Dissociation Drug Exposure Drug usage Early identification Education Environmental Risk Factor Exposure to Future Genetic Genetic Markers Genetic Models Genetic Predisposition to Disease Genetic Risk Goals Human Individual Learning Link Mediating Mediator Mentors Mentorship Methamphetamine Methamphetamine dependence Modeling Molecular Neurobiology Nucleus Accumbens Pathology Pharmaceutical Preparations Phenotype Predisposition Prevention Prevention strategy Principal Investigator 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 Universities Variant Viral addiction addiction liability behavioral phenotyping biomarker identification differential expression drug of abuse early detection biomarkers early life stress experimental study improved insight interest motivated behavior neurotransmission novel novel therapeutic intervention protein expression sorting nexins trafficking translational potential

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 /摘要从毒品使用到滥用，有时再到依赖性的过渡可能是由生物学因素介导的在吸毒之前存在。尽管已知长期暴露于滥用药物会破坏许多信号通路，对介导成瘾易感性的分子机制知之甚少。那里有很大的兴趣识别早期生物标志物以提高成瘾的敏感性预防策略。大多数研究都是在依赖物质的个体中进行的 “敏感性”和“后果”之间的解离是模棱两可的。我最近确定了行为大鼠的表型可靠地预测未来的吸毒行为并确定三种蛋白成瘾易感性的介体：排序Nexin 1（SNX1），Ryanodine受体2（RYR2）和ataxin 2 like （ATXN2L）。这些蛋白质参与细胞内运输，钙信号和细胞骨架重组，并以前与成瘾有关。精确地表达这些表达方式蛋白质会影响信号级联的基本成瘾易感性。总体目标该建议的是确定蛋白质的功能和分子作用敏感性并研究这些因素如何机械地与遗传和/或环境联系起来成瘾风险的组成部分。为了实现这一目标，拟议的研究将结合精致采用病毒，蛋白质组学和生物信息学方法的行为和计算评估。在目标1中我会使用诱导且可逆的病毒构建体来双向操纵SNX1，RYR2和 ATXN2L，还确定SNX1，RYR2和ATXN2L Alter的表达变化如何甲基苯丙胺的自加入和蛋白质信号传导机制。在AIM 2中，我将确定是否变化在SNX1的表达中与增加的成瘾风险有关。在AIM 3中，我将确定SNX1，RYR2的表达变化是否变化在环境添加易感性的模型中，ATXN2L发生了变化，并与增加有关成瘾风险。这些目标的完成将产生对成瘾的信号传导机制的新见解可以确定成瘾风险的早期生物学标志的敏感性，并改善了当前的策略预防成瘾。首席研究人员将接受病毒和技术培训细胞信号传导和细胞机制专家的蛋白质组学技术，以及病毒技术成熟行为。耶鲁大学和系精神病学提供了特殊的设施，完成拟议的实验的资源，并具有卓越的声誉和跟踪记录心理和过渡到早期研究人员到独立研究人员的记录。提议培训，教育和研究将为PI提供技术和专业培训，以成为成功的独立成瘾研究者。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reward-Mediated, Model-Free Reinforcement-Learning Mechanisms in Pavlovian and Instrumental Tasks Are Related.

巴甫洛夫任务和工具任务中的奖励中介、无模型强化学习机制是相关的。

DOI：
10.1523/jneurosci.1113-22.2022
发表时间：
2023
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
MoinAfshar,Neema;Cinotti,François;Martin,David;Khamassi,Mehdi;Calu,DonnaJ;Taylor,JaneR;Groman,StephanieM
通讯作者：
Groman,StephanieM

Astrocytic Activation to Restore Goal-Directed Behaviors.

星形胶质细胞激活以恢复目标导向的行为。