Molecular Basis of RGS Protein Function in the Striatum

描述(申请人提供)：这是NIDA赞助的K02独立科学家奖的申请书。候选人的长期目标是阐明基底节G蛋白信号调节的机制，作为了解神经疾病和成瘾及其治疗方法的必要前提。该研究提案的主要重点是阿片和多巴胺G蛋白信号的中央调节因子RGS9-2，它与成瘾和药物滥用有关。我们最近发现，纹状体中的RGS9-2与一种新的神经元蛋白存在复合体，我们称之为R7结合蛋白(R7BP)。这一假设认为，R7BP通过调控RGS9-2的表达水平、定位和活性，在纹状体神经元中作为RGS9-2功能的关键调节因子。这一假说的具体目的如下：1.确定R7BP控制纹状体神经元RGS9-2表达的机制。2.了解R7BP在调节RGS9-2催化活性中的作用。3.进一步研究纹状体神经元G蛋白失活复合体的分子组成。除了追求研究目标，申请者还计划通过以下方式从事职业发展活动：(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，(Ii)将我的研究计划整合到更大的社区努力中，以了解药物成瘾的机制，以及(Iii)学习研究药物成瘾的尖端行为和成像方法，并将其应用于实验室的研究方向。 与公共健康相关：这些研究应该提供对大脑基底节奖赏处理的调节机制的洞察。这些知识对于更好地理解滥用药物是如何导致成瘾的，以及希望未来治疗干预策略的发展将是重要的。

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.