Mechanisms of alcohol-induced plasticitey mediated by Arf6

Arf6介导的酒精诱导可塑性机制

基本信息

批准号：
9761413
负责人：
Adrian Rothenfluh
金额：
$ 34.31万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761413
关键词：
Acute Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Behavioral Behavioral Assay Biochemical Biological Assay Brain Cell Culture Techniques Cell Surface Receptors Cells Chronic Consumption Coupling Data Dependence Development Disease Dose Drosophila genus Endocytosis Ethanol Experimental Genetics FDA approved FRAP1 gene Face Family GTPase-Activating Proteins Gene Family Genes Goals Growth Guanine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Health Hazards Human Insulin Receptor Laboratories Lead Mediating Mediation Metabolism Molecular Monomeric GTP-Binding Proteins Nervous system structure Neuronal Plasticity Neurons Outcome Pathway interactions Pharmaceutical Preparations Pharmacology Play Publishing Rattus Reaction Receptor Signaling Relapse Research Resistance Ribosomal Protein S6 Kinase Risk Factors Rodent Role Sedation procedure Self Administration Signal Transduction Sirolimus Testing Therapeutic Intervention United States Up-Regulation Vertebrates addiction adverse outcome alcohol abuse therapy alcohol behavior alcohol exposure alcohol response alcohol sensitivity alcohol use disorder base behavioral outcome behavioral response effective therapy experience fly genetic manipulation high risk drinking in vivo insight insulin mediators insulin signaling mTOR Inhibitor neural circuit neuromechanism new therapeutic target novel preference prevent receptor-mediated signaling rho targeted treatment therapeutic target trafficking translational impact vinegar fly

项目摘要

Alcohol abuse disorders (AUD) are a major health hazard that affects millions of people every year in the United States. Repeat alcohol exposure can lead to tolerance, increased preference and consumption. Such behavioral changes, and the accompanying neuronal plasticity, underlie addiction, yet many molecular mechanisms governing these changes remain to be elucidated. Signaling through the insulin receptor (InR) in neurons is known to modify plasticity, but its effects on alcohol-induced behavioral responses are not known. Our goal is to understand the cellular, neural, and circuit mechanisms of Arf6-dependent nervous system InR signaling in alcohol-induced plasticity. This is based on our published data that Arf6 mediates InR signaling in vivo and in cell culture. First, we will determine the mechanisms of Arf6-mediated InR signaling and endocytosis. We will systematically, and comprehensively test the role of two gene families known to directly regulate the function of Arf6. Second, we will determine neural circuits that specifically affect ethanol-induced tolerance and consumption preference, as well as the naïve aversive reactions to alcohol. We will test the role of Arf6 regulators in these circuits in alcohol-induced behavioral responses. Third, we will determine in vivo mechanisms how signaling from the InR pathway can affect distinct alcohol-induced behavioral changes: tolerance, and consumption preference. The genes we propose to investigate are all conserved from Drosophila to humans, and the proposed research will advance our molecular understanding of the mechanisms regulating alcohol-induced behavioral changes. This in turn, will result in the identification of new risk factors and therapeutic targets for the treatment of alcohol abuse disorders.

酒精滥用障碍（AUD）是一种主要的健康危害，每年都会影响数百万人美国。重复酒精暴露会导致耐受性，偏好和消费量增加。这样的行为变化以及参与的神经元可塑性，基础成瘾，但许多分子控制这些变化的机制仍有待阐明。通过胰岛素受体（INR）在中的信号传导已知神经元可以改变可塑性，但其对酒精引起的行为反应的影响尚不清楚。我们的目标是了解ARF6依赖性神经系统INR的细胞，神经和电路机制酒精诱导的可塑性中的信号传导。这是基于我们已发布的数据，该数据ARF6介导INR信号传导体内和细胞培养。首先，我们将确定ARF6介导的INR信号传导和内吞作用。我们将系统地，全面地测试两个已知直接的基因家族的作用调节ARF6的功能。其次，我们将确定特异性影响乙醇诱导的神经回路耐受性和消费偏好，以及对酒精的天真厌恶反应。我们将测试角色这些电路中的ARF6调节剂在酒精引起的行为反应中。第三，我们将确定体内机制来自INR途径的信号传导如何影响不同的酒精引起的行为变化：容忍和消费偏好。我们建议研究的基因都从果蝇对人类，拟议的研究将提高我们对减轻酒精引起的行为变化的机制。反过来，这将导致新的识别危险因素和治疗目标用于治疗酒精滥用障碍。