Molecular mechanisms of susceptibility to drug use

吸毒易感性的分子机制

• 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
• 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

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 从吸毒到滥用，最终到依赖的转变可能是由生物因素促成的。 在吸毒前就已经存在了。尽管众所周知，长期接触滥用药物会扰乱许多人 在信号通路方面，人们对介导成瘾易感性的分子机制知之甚少。那里 对识别成瘾易感性的早期生物标志物以改善成瘾有相当大的兴趣 预防策略。大多数研究都是在依赖物质的个人中进行的，在这些人中 “易感性”和“后果”之间的区别是模糊的。我最近发现了一个行为 可靠地预测未来吸毒行为的大鼠的表型，并确定三种蛋白质为潜在的 成瘾易感性的介质：分类连接蛋白1(SNX1)、兰诺定受体2(RYR2)和类阿塔克辛2 (ATXN2L)。这些蛋白参与细胞内转运、钙信号和细胞骨架。 重组，以前曾被认为与上瘾有关。确切地说，这些基因表达的差异 蛋白质影响成瘾易感性的信号级联尚不清楚。首要目标是 这一建议的目的是确定介导成瘾的蛋白质的功能和分子作用。 并研究这些因素如何与遗传和/或环境有机械联系 成瘾风险的组成部分。为了实现这一目标，拟议的研究将结合复杂的 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。在《目标1》中我会 使用可诱导和可逆的病毒构建物双向操作SNX1、RYR2和 ATXN2L，并确定SNX1、RYR2和ATXN2L的表达变化如何改变 甲基苯丙胺自我给药和蛋白质信号机制。在目标2中，我将确定变异是否 在遗传成瘾易感性模型中SNX1、RYR2和ATXN2L的表达发生改变，并且是 与更高的成瘾风险相关。在目标3中，我将确定SNX1，RYR2， ATXN2L在环境成瘾易感性模型中发生改变，并与 上瘾的风险。这些目标的完成将对成瘾的信号机制产生新的见解 易感性，可以识别成瘾风险的早期生物标志物，并改进目前的策略 预防上瘾。首席调查员将接受病毒和病毒方面的指导和技术培训 由细胞信号和细胞机制专家提供的蛋白质组技术，以及 有动机的行为。耶鲁大学和精神病学系提供特殊的设施和 用于完成建议实验的资源，以及拥有卓越声誉和跟踪的资源 指导早期调查人员并将其过渡到独立调查人员的记录。建议数 培训、教育和研究将为PI提供技术和专业培训，使其成为一名 成功的独立成瘾调查员。