1/11 Integrative Neuroscience Initiative on Alcoholism

项目摘要 这是酒精中毒综合神经科学倡议（INIA）的竞争性更新申请- 神经免疫联盟（通知# RFA-AA-20-011，RFA-AA-20-013）整合多学科研究 基于与过量酒精相关的基因组、细胞和行为神经适应的项目 消费这个联盟已经确定了与过量酒精相关的基因网络和途径 饮酒在人类和动物中的作用，并专注于神经免疫和 神经炎症信号通路。在这一倡议的下一阶段，我们的集体建议将解决 几个记录的NIAAA目标，其中包括：1）了解基因组学，电生理学， 神经元和神经胶质细胞中脑免疫信号系统的药理学及其在病因和 酒精依赖的治疗; 2）使用新技术如单细胞和空间转录组学， 蛋白质组学和多模式功能和结构成像来研究这些系统; 3）促进 通过在多个实验室和多个测定中进行测试，数据的再现性和转换; 4）指导 研究者确定NIAAA临床前和临床研究结果的可翻译性- 联合体以外的支持单位。INIA-N的总体假设是， 神经免疫机制将为治疗与酒精相关的过度饮酒提供信息 使用Disorder。10个研究部门和一个行政核心组成了该联盟。INIA-N将是 由行政核心与执行委员会和指导委员会合作指导， 杰出的科学顾问委员会行政核心将提供领导、监督 科学项目以及项目数据的整合和翻译。INIA-N有六个目标：1）扩展基因 表达数据集与来自单核测序和空间转录组学的结果，以生成细胞类型 特异性和解剖学转录组图谱以及整合的人细胞转录组数据与人 全基因组关联研究; 2）确定特定非神经元细胞类型（星形胶质细胞和 小胶质细胞）的分子和行为的影响，过量饮酒，通过合作 研究脑内免疫相关细胞; 3）研究酒精诱导的神经元周围网络的变化 以及细胞外基质蛋白的丰度和翻译后修饰作为 神经胶质-神经元串扰，影响大脑回路调节酒精消费; 4）追求生物化学和 细胞因子信号传导的电生理学研究，以了解先天免疫机制， 过量饮酒会改变大脑功能; 5）应用系统水平的连接组学方法， 确定过量饮酒改变整个大脑功能的机制，重点是 我们顶级神经免疫基因的作用; 6）提出并优先考虑药物靶点和化合物， 由NIAAA支持的INIA-N联盟以外的实体推进动物和人类试验。

PROJECT SUMMARY This is a competing renewal application for the Integrative Neuroscience Initiative on Alcoholism (INIA)- Neuroimmune consortium (Notice# RFA-AA-20-011, RFA-AA-20-013) to integrate multidisciplinary research projects based on the genomic, cellular, and behavioral neuroadaptations related to excessive alcohol consumption. This consortium has identified gene networks and pathways associated with excessive alcohol drinking in humans and animals and focuses on potential drug targets within neuroimmune and neuroinflammatory signaling pathways. In the next phase of this initiative, our collective proposals will address several documented NIAAA goals which include: 1) understanding the genomics, electrophysiology, and pharmacology of brain immune signaling systems in neurons and glial cells and their role in causes and treatments of alcohol dependence; 2) using new technologies such as single cell and spatial transcriptomics, proteomics, and multimodal functional and structural imaging to study these systems; 3) promoting reproducibility and translation of data through testing in multiple laboratories and in multiple assays; 4) guiding investigators in determining the translatability of their findings for preclinical and clinical studies by NIAAA- supported units outside the consortium. The overall hypothesis for INIA-N is that systematic analysis of neuroimmune mechanisms will inform strategies for treatment of excessive drinking associated with Alcohol Use Disorder. Ten Research Components 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, and integration and translation of project data. INIA-N has six goals: 1) expand gene expression datasets with results from single nuclei sequencing and spatial transcriptomics to generate cell-type specific and anatomical transcriptome maps and integrate human cellular transcriptome data with human genome wide association studies; 2) define the contribution of specific non-neuronal cell types (astrocytes and microglia) to the molecular and behavioral effects of excessive alcohol consumption through a collaborative investigation of immune related cells of the brain; 3) examine alcohol-induced changes in perineuronal nets and in the abundance and post-translational modifications of extracellular matrix proteins as mechanisms for glial-neuronal cross talk that impact brain circuits regulating alcohol consumption; 4) pursue biochemical and electrophysiological studies of cytokine signaling to understand innate immune mechanisms by which excessive alcohol consumption changes brain function; 5) apply systems-level, connectomics approaches to identify mechanisms by which excessive alcohol consumption changes whole brain function, with emphasis on the role of our top neuroimmune genes; and 6) propose and prioritize drug targets and compounds for advancement to testing in animals and in humans by NIAAA supported entities outside the INIA-N consortium.