Molecular investigations of the TRIF-dependent pathway in alcohol abuse

项目摘要/摘要 酒精使用障碍(AUD)影响着数以百万计的人，给社会带来巨大的社会经济负担。 尽管酒精依赖对社会经济和健康有影响，但目前只有三种治疗方法 被批准用于AUD，只有适度的效果。目前，分子机制有助于 导致酒精耐受、依赖和戒断的神经适应性变化尚不完全清楚。 因此，了解从受控饮酒向饮酒转变的分子机制 为了确定新的药物靶点以推进AUDS的治疗，依赖是至关重要的。近期 有证据表明，酒精对大脑中促炎性Toll样受体(TLR)信号的调节失调。 药物或基因操作的TLR信号通路减少酒精摄入量和 偏好--提示神经免疫信号可能是治疗的有效靶点 AUD的数量。因此，建议的研究将探讨一种未被探索的分子机制 TLR信号通路的分支(TRIF依赖)及其在酒精滥用中的作用。第一个目标将使用 质谱学和磷蛋白质组学确定酒精是如何改变神经免疫激酶活性的 以及大脑中的全球基因组。第二和第三个目标将使用零突变，即病毒介导的基因 操作和小鼠行为模型来测试TRIF依赖的信号在调节中的功能作用 乙醇消耗量。因此，建议的研究旨在研究TRIF依赖的信号转导AS 尚未开发的药物开发和基因研究新靶点的来源。 这项研究将提供关于一种未知的神经免疫途径及其作用的关键新知识。 酗酒。AIM 1的结果将确定酒精使用障碍的全球激酶失调，这将 促进新的药理靶点的开发。这项研究还将确定哪些信号 依赖TRIF的神经免疫信号通路的组成部分对乙醇的调节至关重要 消费。通过了解依赖TRIF的信号转导如何促进减少酒精消耗， 该项目的结果将蕴含有趣的新药理靶点，并有助于发现 可能有助于酒精中毒的启动、维持或进展的新基因和新途径。 此外，这项研究的结果可能会扩展到其他与激酶有关的成瘾和疾病 调节失调和神经免疫信号，如缺血、阿尔茨海默病、多发性硬化症、 帕金森氏症和创伤性脑损伤。因此，了解常见的信号通路提供了一种 开发治疗多种疾病的治疗剂的机会，从而 提高个别患者的生活质量。

Project Summary/Abstract Alcohol use disorders (AUDs) affect millions of people and burdens society with large socioeconomic costs. Despite the socioeconomic and health impact of alcohol dependence, there are only three treatments currently approved for AUDs, which are only modestly effective. Currently, the molecular mechanisms contributing to neuroadaptive changes that result in alcohol tolerance, dependence, and withdrawal are not fully understood. Thus, understanding the molecular mechanisms underlying the transition from controlled drinking to alcohol dependence is crucial in order to identify novel drug targets to advance the treatment of AUDs. Recent evidence suggests that alcohol dysregulates pro-inflammatory toll-like receptor (TLR) signaling in the brain. Pharmacological or genetic manipulation of the TLR signaling pathway reduces alcohol intake and preference—suggesting that neuroimmune signaling could be an effective therapeutic target for the treatment of AUDs. Therefore, the proposed research will investigate the molecular mechanisms of an unexplored branch of the TLR signaling pathway (TRIF-dependent) and its role in alcohol abuse. The first aim will use mass spectrometry and phosphoproteomics to determine how alcohol alters neuroimmune kinase activity as well as the global kinome in brain. The second and third aim will use null mutants, viral-mediated gene manipulation and mouse behavioral models to test the functional role of TRIF-dependent signaling in regulation of ethanol consumption. Thus, the proposed studies were designed to investigate TRIF-dependent signaling as an untapped source of new targets for drug development and genetic study. This study will provide crucial new knowledge about an unexplored neuroimmune pathway and its role in alcohol addiction. Results from Aim 1 will determine global kinase dysregulation in alcohol use disorder that will facilitate development of new pharmacological targets. This study will also determine which signaling components of the TRIF-dependent neuroimmune signaling pathway are critical for regulation of ethanol consumption. By understanding how TRIF-dependent signaling can facilitate decreased alcohol consumption, results from this project will implicate interesting new pharmacological targets and facilitate the discovery of novel genes and pathways that might contribute to the initiation, maintenance, or progression of alcoholism. Furthermore, the results of this research may extend to other addictions and diseases that involve kinase dysregulation and neuroimmune signaling, such as ischemia, Alzheimer's Disease, Multiple sclerosis, Parkinson's disease, and traumatic brain injury. Thus, understanding common signaling pathways provides an opportunity for developing therapeutic agents that will work in the treatment of multiple conditions, thereby increasing the quality of life for individual patients.