Molecular Basis of RGS Protein Function in the Striatum

 描述(申请人提供)：这是NIDA赞助的K02独立科学家奖的续展申请。候选人是佛罗里达州斯克里普斯研究所神经科学系的终身副教授。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。下一阶段拟议的研究将集中于描绘纹状体关键RGS蛋白：RGS9-2和RGS7调节细胞信号的机制。我们最近的发现表明，这两个RGS蛋白的功能紧密交织在一起。它们以大分子复合体的形式存在，与几个结合伙伴结合，并在药物暴露时发生显着的重塑，以及神经元兴奋性的变化，表明RGS系统的可塑性有助于导致成瘾的分子适应。具体地说，这项研究将试图(1)确定RGS复合体成分之间的相互作用如何有助于阿片类药物和可卡因的行为反应，(2)描绘RGS在G蛋白通路中作用的分子特异性，以及(3)了解RGS复合体与腺苷酸环化酶信号整合的机制，腺苷环化酶信号是参与成瘾的关键第二信使系统。为解决这些目标而提出的战略将需要遗传、行为、生化和生理方法的协同组合，利用一系列强大的试剂和动物模型的存在。除了科学指导外，申请者还将专注于职业发展活动，包括通过与合作研究人员团队的密切互动进行新方法和技术方面的培训，参加社区外联活动，建立药物成瘾研究英才中心，以及积极参与与负责任的研究行为问题有关的活动。K02奖将通过允许继续专注于毒瘾研究并保护候选人免受过度教学和管理的影响，在推进马尔特米亚诺夫博士的职业生涯中发挥重要作用。

 DESCRIPTION (provided by applicant): This is a renewal application for the NIDA sponsored K02 Independent Scientist Award. The candidate is a tenured Associate Professor in the Department of Neuroscience at the Scripps Research Institute - Florida. 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. Proposed studies during the next period will focus on delineating the mechanisms by which key striatal RGS proteins: RGS9-2 and RGS7 regulate cellular signaling. Our recent findings indicate that the function of the two RGS proteins is closely intertwined. They exist as macromolecular complexes with several binding partners and undergo striking remodeling upon drug exposure as well as changes in neuronal excitability suggesting that plasticity in the RGS system contributes to molecular adaptations leading to addiction. Specifically, the research will seek to (1) to establish how interplay between RGS complex components contribute to behavioral response to opioids and cocaine, (2) delineate molecular specificity of RGS action in G protein pathways and (3) understand the mechanisms behind the integration of RGS complexes with the adenylyl cyclase signaling, the key second messenger system implicated in addiction. The strategy proposed to address these Aims will entail a synergistic combination of genetic, behavioral, biochemical, and physiological approaches, exploiting the existence of a powerful array of reagents and animal models. In addition to the scientific directions, the applicant will focus on career development activities tht will include training in emerging approaches and techniques through close interactions with a team of collaborating investigators, participation in community outreach events, building a center of excellence in drug addiction research and active engagement in activities pertaining to issues in responsible conduct of research. The K02 award will play an essential role in advancing Dr. Martemyanov's career by allowing continued focus on drug addiction research and protecting the candidate from excessive teaching and administration.