Molecular Basis of RGS Protein Function in the Striatum

描述（由申请人提供）：这是NIDA赞助的K 02独立科学家奖的申请。候选人的长期目标是阐明基底神经节中G蛋白信号调节的机制，作为理解神经系统疾病和成瘾以及开发治疗方法的必要先决条件。该研究提案的主要重点是阿片类和多巴胺G蛋白信号传导的中央调节因子RGS 9 -2，它与成瘾和药物滥用有关。我们最近发现纹状体中的RGS 9 -2与一种新的神经元蛋白R7结合蛋白（R7 BP）复合存在。该提议提出的假设是，R7 BP通过控制RGS 9 -2的表达水平、定位和活性，在纹状体神经元中充当RGS 9 - 2功能的关键调节剂。这一假设将在以下具体目标中得到解决：1.以确定R7 BP控制纹状体神经元中RGS 9 -2表达的机制。2.了解R7 BP在调节RGS 9 -2催化活性中的作用。3.进一步研究纹状体神经元G蛋白失活复合物的分子组成。除了追求研究目标外，申请人计划通过以下方式开展职业发展活动：（I）与专注于药物成瘾机制的领先研究人员建立和/或保持积极的合作，（二）将我的研究计划融入更大的社区努力，以了解药物成瘾的机制;（三）学习尖端的行为和成像方法来研究药物成瘾，并将其植入实验室以追求研究方向。 公共卫生相关性：这些研究应该提供一个深入了解机制，调节奖励处理在基底神经节的大脑。这些知识对于更好地理解药物滥用如何导致成瘾以及未来治疗干预策略的发展具有重要意义。

DESCRIPTION (provided by applicant): This is an application for the NIDA sponsored K02 Independent Scientist Award. The long term goal of the candidate is to elucidate the mechanisms of G protein signaling regulation in the basal ganglia as a necessary prerequisite to understanding neurological diseases and addiction and developing means of their treatment. The main focus of the research proposal is on the central regulator of opioid and dopamine G protein signaling, RGS9-2 that has been implicated in addiction and drug abuse. We have recently discovered that RGS9-2 in the striatum exists in a complex with a novel neuronal protein which we named R7 Binding Protein (R7BP). The HYPOTHESIS addressed by this proposal is that R7BP serves as a critical regulator of RGS9-2 function in the striatal neurons by controlling the expression level, localization, and activity of RGS9-2. This hypothesis will be addressed in the following SPECIFIC AIMS: 1. to determine the mechanisms by which R7BP controls expression of RGS9-2 in striatal neurons. 2. To understand the role of R7BP in the regulation of RGS9-2 catalytic activity. 3. To further characterize the molecular composition of G protein inactivating complex in striatal neurons. In addition to pursuing the research goals, the applicant plans to undertake career development activities by: (I) establishing and/or maintaining active collaborations with leading researchers focusing on drug addiction mechanisms, (II) integrating my research program into the larger community efforts to understand mechanisms of drug addiction and (III) learning cutting edge behavioral and imaging approaches to study drug addiction and implanting them to pursue the research directions in the laboratory. PUBLIC HEALTH RELEVANCE: The studies should provide an insight into the mechanisms that regulate reward processing in the basal ganglia of the brain. This knowledge will be important for better understanding of how drugs of abuse lead to addiction with the hopes for the future development of therapeutical intervention strategies.