Integrative Neuroscience Initiative on Alcoholism

关于酗酒的综合神经科学倡议

• 批准号: 9242459
• 负责人: Robert A Harris
• 金额: $ 48.1万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242459
• 关键词: Address; Alcohol consumption; Alcohol dependence; Alcoholism; Animals; Basic Science; Behavioral; Behavioral Assay; Biological; Biological Assay; Brain; Brain imaging; Candidate Disease Gene; Clinical; Collaborations; Communication; Data; Data Set; Databases; Development; Drug Targeting; Electrophysiology (science); Ensure; Evaluation; FDA approved; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Goals; Heavy Drinking; Human; Immune; Immune signaling; Interdisciplinary Study; Laboratories; Laboratory Study; Leadership; Link; Measures; Modeling; Mutation; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neuroimmune; Neurosciences; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Privatization; Progress Reports; Publications; RNA Splicing; Reproducibility; Research; Research Design; Research Personnel; Research Project Grants; Resource Sharing; Resources; Rodent; Rodent Model; Role; Scientist; Stress; Structure; System; Testing; Texas; Time; Translating; Translations; Untranslated RNA; Update; Validation; Variant; alcohol abuse therapy; alcohol research; alcohol use disorder; base; behavior test; computerized tools; computing resources; conflict resolution; data access; data management; data sharing; design; drinking; drug candidate; drug testing; genome wide association study; meetings; multidisciplinary; neural circuit; neuroadaptation; neuroinflammation; new technology; nonhuman primate; novel; research study; response; sex; small molecule; symposium; transcriptome sequencing; treatment strategy; web site

PROJECT SUMMARY This is a competing renewal application for the Integrative Neuroscience Initiative on Alcoholism (INIA)- Neuroimmune consortium (Notice# RFA-AA-16-004/005/006) to identify drug targets based on the genomic, cellular, and behavioral neuroadaptations related to excessive alcohol consumption. INIA-Neuroimmune (INIA- N) will address several NIAAA goals, including: 1) understanding the genomics, electrophysiology, and pharmacology of brain immune pathways and their role in alcohol use disorders (AUDs); 2) using new technologies to study neural circuits involved in excessive alcohol drinking; 3) promoting data reproducibility and translation through testing in multiple species (including humans), multiple laboratories, and multiple assays; 4) using emerging computational resources that connect gene networks to drugs to identify compounds with potential to reduce excessive drinking. A key goal for INIA-N is to probe cross-species genomic datasets, together with novel computational approaches, to predict FDA-approved drugs that can be repurposed to treat AUDs. The overall hypothesis for INIA-N is that excessive alcohol consumption causes genetic changes and neuroadaptations in immune-related pathways that are conserved across multiple species (including humans), allowing for the systematic selection and testing of drug targets from the computational to the clinical level. Ten Research Components, two Scientific Cores, and an Administrative Core comprise the consortium. INIA-N will be directed by the Administrative Core in cooperation with the Executive and Steering Committees and guided by a distinguished Scientific Advisory Board. The Administrative Core will provide leadership, oversight of scientific projects, authentication of study drugs, and integration and translation of project data. INIA-N has four goals: 1) Expand our rodent and human genomic studies to include non-human primates (in collaboration with INIA-Stress) and new rodent models, and integrate these with existing datasets. We will also integrate genetic (genome-wide association studies) and genomic analyses (new human RNA-Seq datasets) to facilitate drug target identification, with an emphasis on neuroimmune targets and the unexplored role of novel non-coding RNAs and splice variants in alcohol consumption; 2) Combine extensive genomic resources with new computational approaches to identify candidate drugs that may be repurposed to treat AUDs. These drugs will be tested in several animal drinking models; 3) Apply systems-level approaches (electrophysiology and live brain imaging) to understand how excessive drinking changes brain function, with an emphasis on our top neuroimmune targets; 4) Select leading candidates that emerge from rigorous behavioral and functional testing to study in the new human laboratory component. INIA-N research encompasses a unique `gene network to pharmacotherapy' approach to apply cutting-edge computational tools to nominate gene targets and drugs from our extensive genomic databases and systematically test these candidates in functional and behavioral assays.

项目摘要 这是对酒精中毒综合神经科学倡议（INIA）的竞争更新应用 - 神经免疫财团（通知＃RFA-AA-16-004/005/006），以基于基因组为基础的药物靶标 细胞和与饮酒过量有关的行为神经适应。 inia-neurommune（inia- n）将解决几个NIAAA目标，包括：1）了解基因组学，电生理学和 脑免疫途径的药理学及其在酒精使用障碍中的作用（AUDS）； 2）使用新 研究与过量饮酒有关的神经回路的技术； 3）促进数据可重复性 通过在多种物种（包括人类），多个实验室和多个物种中进行测试的翻译 测定； 4）使用将基因网络与药物联系起来的新兴计算资源以识别 具有减少过量饮酒的潜力的化合物。 INIA-N的关键目标是探测跨物种 基因组数据集以及新型的计算方法，以预测可以是FDA批准的药物 重新利用以治疗auds。 INIA-N的总体假设是过多的饮酒原因 免疫相关途径中的遗传变化和神经照顾，这些途径在多个途径上保守 物种（包括人类），允许从 计算到临床水平。十个研究组件，两个科学核心和一个行政 核心包括财团。 INIA-N将由行政核心与 执行和指导委员会，并由杰出的科学顾问委员会指导。这 行政核心将提供领导，对科学项目的监督，研究药物的认证以及 项目数据的集成和翻译。 Inia-N有四个目标：1）扩展我们的啮齿动物和人类基因组 研究包括非人类灵长类动物（与Inia termworks合作）和新的啮齿动物模型，以及 将这些与现有数据集集成在一起。我们还将整合遗传学（全基因组关联研究）和 基因组分析（新的人RNA-SEQ数据集）促进药物靶标识别，重点是 神经免疫靶标和新型非编码RNA和剪接变体在酒精中的作用未开发的作用 消耗; 2）将广泛的基因组资源与新的计算方法相结合以识别 可以重新使用以治疗auds的候选药物。这些药物将在几种动物喝酒中进行测试 模型； 3）应用系统级方法（电生理学和活脑成像）来了解如何 过度饮酒会改变大脑功能，重点是我们的顶级神经免疫靶标。 4）选择 从严格的行为和功能测试中出现的领先候选人到新人类的研究 实验室组件。 INIA-N研究包括独特的“基因网络到药物疗法”方法 应用尖端计算工具来提名我们广泛的基因组中的基因靶标和药物 数据库并系统地测试这些候选者在功能和行为测定中。