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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.

项目总结/摘要从药物使用到滥用并最终到依赖的转变可能是由生物因素介导的在吸毒前就存在的尽管众所周知，长期接触滥用药物会扰乱许多人的健康信号通路，对介导成瘾易感性的分子机制知之甚少。那里对鉴定成瘾易感性的早期生物标志物以改善成瘾性是相当感兴趣的预防战略。大多数研究都是在物质依赖者中进行的， “易感性”和“后果”之间的分离是模糊的。我最近发现了一种行为在大鼠中的表型，可靠地预测未来的吸毒行为，并确定了三种蛋白质作为潜在的成瘾易感性介质：分类连接蛋白1（SNX 1）、兰尼碱受体2（RYR 2）和共济失调蛋白2样（ATXN2L）。这些蛋白质参与细胞内运输、钙信号传导和细胞骨架重组，以前与成瘾有关。这些基因表达的差异蛋白质影响成瘾易感性潜在的信号级联尚不清楚。总体目标这项提议的一个重要目的是确定介导成瘾的蛋白质的功能和分子作用易感性，并研究这些因素是如何与遗传和/或环境成瘾风险的组成部分。为了实现这一目标，拟议的研究将联合收割机使用病毒、蛋白质组学和生物信息学方法进行行为和计算评估。目标1我会使用可诱导和可逆的病毒构建体双向操纵SNX 1、RYR 2和 ATXN 2L，并确定SNX 1，RYR 2和ATXN 2L表达的变化如何改变甲基苯丙胺自我管理和蛋白质信号传导机制。在目标2中，我将确定变化是否 SNX 1、RYR 2和ATXN 2L的表达在遗传成瘾易感性模型中发生改变，与成瘾风险增加有关。在目标3中，我将确定SNX 1，RYR 2，和ATXN 2L在环境成瘾易感性模型中改变，并与增加的成瘾风险这些目标的完成将产生对成瘾信号机制的新见解易感性，可以识别成瘾风险的早期生物标志物，并改善目前的策略，预防成瘾。主要研究者将接受病毒和蛋白质组学技术由细胞信号传导和细胞机制方面的专家，以及病毒技术，动机行为。耶鲁大学和精神病学系提供卓越的设施，资源完成拟议的实验，以及具有特殊的声誉和跟踪指导早期研究者并将其转变为独立研究者的记录。拟议培训、教育和研究将为PI提供技术和专业培训，使其成为成功的独立成瘾调查员

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

Adolescent reinforcement-learning trajectories predict cocaine-taking behaviors in adult male and female rats.