Regulation of Excessive Alcohol Consumption by the Lmo-Alk Axis

描述(申请人提供)：本项目的目标是研究四个基因在酗酒和酒精依赖啮齿动物模型中的功能。这些基因包括编码转录调节因子的Lmo3和Lmo4，编码受体酪氨酸激酶的alk，以及编码调节alk基因产物的配体的mdk。研究人员实验室和INIA-West联盟其他成员的实验室的初步工作表明，这四个基因相互协作，调节与过度饮酒相关的行为。这项拟议的工作包括四种类型的实验：(1)在基因工程小鼠中进行行为研究，以关键地测试这四个基因在酒精相关行为中的作用；(2)实验，以绘制这些基因发挥作用的大脑区域；(3)实验，以确定酒精是否影响这些基因的表达和功能；以及(4)实验，以确定这些基因发挥作用的下游途径。这项工作将为新的信号通路在控制模拟人类酗酒的行为中所起的作用提供基本的见解。此外，该途径中的一些基因是蛋白激酶，被认为是药物开发的极佳靶点。因此，该项目的成功完成将为开发全新的、亟需的人类酒精滥用药物疗法奠定基础。

DESCRIPTION (provided by applicant): The goal of this project is to study the function of four genes in rodent models of binge drinking and ethanol dependence. The genes include Lmo3 and Lmo4, which encode transcriptional regulators, Alk, which encodes a receptor tyrosine kinase, and Mdk, which encodes a ligand that regulates the Alk gene product. Preliminary work in the investigator's laboratory and in the laboratories of other members of the INIA-West consortium suggests that these four genes cooperate to regulate behaviors associated with excessive alcohol consumption. The proposed work includes four types of experiments: (1) behavioral studies in genetically engineered mice to critically test the role of these four genes in alcohol-related behaviors, (2) experiments to map the brain regions where these genes function, (3) experiments to determine if alcohol affects the expression and function of these genes, and (4) experiments to identify downstream pathways by which these genes exert their effects. The work will provide basic insights into the role of a new signaling pathway in controlling behaviors that model human alcohol abuse. In addition, some of the genes in the pathway are protein kinases, which are regarded as excellent targets for drug development. Successful accomplishment of the project will thus lay the groundwork for development of totally novel, and much needed, pharmacotherapies for alcohol abuse in humans.