Molecular investigations of the TRIF-dependent pathway in alcohol abuse

酒精滥用中 TRIF 依赖性途径的分子研究

• 批准号: 9255693
• 负责人: Anna Warden
• 金额: $ 3.93万
• 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: 2017-01-16 至 2020-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9255693
• 关键词: Address; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alzheimer' s Disease; Behavioral Model; Brain; Brain region; Chronic; Dependence; Development; Disease; Drug Targeting; Elements; Ethanol; Gene Activation; Gene Expression; Gene Targeting; Genes; Genetic study; Genomics; Goals; Health; Heavy Drinking; Human; Immunohistochemistry; Inflammatory; Inflammatory Response; Interferon-beta; Interferons; Investigation; Ischemia; Knock-out; Knowledge; Lead; Maintenance; Mass Spectrum Analysis; Mediating; Messenger RNA; Modification; Molecular; Multiple Sclerosis; Mus; Mutant Strains Mice; Myelogenous; Nuclear; Parkinson Disease; Pathway interactions; Phosphotransferases; Prefrontal Cortex; Production; Publishing; Quality of life; Receptor Activation; Receptor Signaling; Regulation; Research; Role; Signal Pathway; Signal Transduction; Societies; Source; Subfamily lentivirinae; TLR3 gene; Testing; Therapeutic; Therapeutic Agents; Toll-Like Receptor Pathway; Toll-like receptors; Traumatic Brain Injury; Viral; Withdrawal; Work; abstracting; addiction; alcohol exposure; alcohol use disorder; animal facility; chronic alcohol ingestion; cost; cytokine; design; differential expression; drinking; drinking behavior; drug development; effective therapy; frontal lobe; genetic manipulation; individual patient; insight; interest; knock-down; mutant; new therapeutic target; novel; novel therapeutics; phosphoproteomics; preference; problem drinker; protein expression; response; small hairpin RNA; socioeconomics; targeted treatment; therapeutic target; transcription factor

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.

项目总结/摘要 酒精使用障碍（AUDs）影响着数百万人，并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。 批准用于AUD，其仅适度有效。目前，分子机制有助于 导致酒精耐受性、依赖性和戒断的神经适应性变化尚未完全了解。 因此，了解从控制饮酒到酒精的转变的分子机制 依赖性是至关重要的，以确定新的药物靶点，以推进治疗AUD。最近 有证据表明，酒精使大脑中的促炎性Toll样受体（TLR）信号传导失调。 TLR信号通路的药理学或遗传学操作减少了酒精摄入， 这表明神经免疫信号可能是治疗的有效治疗靶点 的AUD。因此，拟议的研究将调查一个未探索的分子机制， TLR信号通路的分支（TRIF依赖性）及其在酒精滥用中的作用。第一个目标将使用 质谱和磷酸蛋白质组学来确定酒精如何改变神经免疫激酶活性， 以及脑中的全局激酶组。第二个和第三个目标将使用无效突变体，病毒介导的基因 操作和小鼠行为模型，以测试TRIF依赖性信号传导在调节中的功能作用 乙醇消费。因此，所提出的研究旨在研究TRIF依赖性信号传导， 为药物开发和基因研究提供了一个尚未开发的新靶点。 这项研究将提供关于未探索的神经免疫途径及其在 酒精成瘾目标1的结果将确定酒精使用障碍中的整体激酶失调， 促进新药理学靶点的开发。这项研究还将确定哪些信号 TRIF依赖性神经免疫信号通路的组分对于乙醇的调节至关重要。 消费通过了解TRIF依赖性信号传导如何促进减少酒精消耗， 该项目的结果将涉及有趣的新药理学靶点，并有助于发现 可能有助于酗酒的启动、维持或进展的新基因和途径。 此外，这项研究的结果可能会扩展到其他成瘾和疾病，涉及激酶 失调和神经免疫信号传导，如缺血，阿尔茨海默病，多发性硬化， 帕金森氏症和脑外伤。因此，了解共同的信号通路提供了一个 这为开发治疗多种病症的治疗剂提供了机会， 提高患者个体的生活质量。