ROLE OF THE STRIATAL-SPECIFIC RGS PROTEIN RGS9-2, IN CELLULAR SIGNALING PATHWAYS

纹状体特异性 RGS 蛋白 RGS9-2 在细胞信号传导通路中的作用

• 批准号: 8360080
• 负责人: Abraham Kovoor
• 金额: $ 8.66万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360080
• 关键词: Adverse effects; Behavioral Research; Biomedical Research; Cell physiology; Chronic; Clinical Research; Corpus striatum structure; Coupling; Data; Dopamine D2 Receptor; Drug-Induced Dyskinesia; Dyskinetic syndrome; Funding; Genes; Grant; Ion Channel; Knockout Mice; Lead; Maps; Mediating; Movement; Mutation; N-Methyl-D-Aspartate Receptors; National Center for Research Resources; Neurons; Parkinson Disease; Patients; Pharmaceutical Preparations; Pharmacotherapy; Principal Investigator; RGS Proteins; Research; Research Infrastructure; Resources; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Source; Surface; Testing; United States National Institutes of Health; Variant; abnormal involuntary movement; computerized data processing; cost; reconstitution

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have provided data suggesting a role for RGS9-2 in the striatal control of movement and in the movement's side-effects of the pharmacotherapy of schizophrenia and Parkinson's disease. For example we showed that RGS9 knockout mice develop abnormal movements that closely resemble drug-induced dyskinesias (DID). DID are unexplained movement side-effects of the pharmacotherapy of Parkinson's disease and schizophrenia, and are thought to result from the chronic actions of the respective drugs on striatal D2-dopamine receptors (D2R). In addition we showed that RGS9-2 targets to D2R and proposed that RGS9-2 either functionally or spatially compartmentalizes D2R in striatal neurons. Thus drug-induced alterations in RGS9-2 mediated striatal D2R cellular compartmentalization may lead to abnormal striatal signal processing and to drug-induced abnormal involuntary movements. Determining how such compartmentalization is altered will require a better understanding of the D2R-RGS9-2 interaction suggested by our previous studies. Thus we will continue with our studies that will test if the targeting RGS9-2 toD2R involves a direct or indirect interaction and map the interacting surfaces. We will also attempt to reconstitute coupling between D2R and ion channels, such as NMDA-receptors that generate and shape striatal signals. We will test if co-expressed RGS9-2 can alter D2R-channel coupling. From a parallel clinical study we have identified non-synonymous mutations and intronic deletions in the RGS9 gene that are enriched in patients with schizophrenia and Parkinson's disease. Thus we will test the hypothesis that these RGS9 gene variations produce alterations in RGS9-2 cellular functions.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们提供的数据表明，RGS9-2在纹状体运动控制以及精神分裂症和帕金森病药物治疗的运动副作用中发挥作用。例如，我们发现RGS9基因敲除小鼠的异常运动与药物诱导的运动障碍(DID)非常相似。DID是帕金森氏病和精神分裂症药物治疗的不明原因的运动副作用，被认为是各自药物对纹状体D2-多巴胺受体(D2R)的慢性作用的结果。此外，我们发现RGS9-2靶向D2R，并提出RGS9-2在功能或空间上对纹状体神经元中的D2R进行分区。因此，药物诱导的RGS9-2介导的纹状体D2R细胞区划的改变可能导致纹状体信号处理的异常和药物诱导的异常不自主运动。要确定这种分区是如何改变的，需要更好地理解我们以前的研究所建议的D2R-RGS9-2相互作用。因此，我们将继续我们的研究，测试靶向RGS9-2到D2R是否涉及直接或间接的相互作用，并绘制相互作用的表面。我们还将尝试重建D2R和离子通道之间的耦合，例如产生和塑造纹状体信号的NMDA受体。我们将测试共表达的RGS9-2是否可以改变D2R通道耦合。从一项平行的临床研究中，我们发现RGS9基因中的非同义突变和内含子缺失在精神分裂症和帕金森病患者中丰富。因此，我们将检验这一假设，即这些RGS9基因变异会导致RGS9-2细胞功能的变化。