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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 我们提供的数据表明，RGS9-2在运动的纹状体控制以及精神分裂症和帕金森氏病的药物疗法的副作用中发挥了作用。例如，我们表明RGS9基因敲除小鼠会形成异常运动，与药物诱导的运动障碍（ID）非常相似。 DID是帕金森氏病和精神分裂症药物治疗的无法解释的运动副作用，被认为是由于各个药物对纹状体D2多巴胺受体（D2R）的长期作用而产生的。此外，我们表明RGS9-2对D2R的靶标，并提出RGS9-2在功能或空间上对纹状体神经元中的D2R进行了分离。因此，药物诱导的RGS9-2介导的纹状体D2R细胞分室化的改变可能导致异常的纹状体信号处理和药物诱导的异常非自愿运动。确定如何改变这种隔室化将需要更好地理解我们以前的研究提出的D2R-RGS9-2相互作用。因此，我们将继续进行研究，以测试目标RGS9-2 TOD2R是否涉及直接或间接相互作用并绘制相互作用的表面。我们还将尝试在D2R和离子通道之间重新建立耦合，例如生成和形状纹状体信号的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，我们发现了RGS9基因中的非同义突变和内含子缺失，这些突变富含精神分裂症和帕金森氏病的患者。因此，我们将检验以下假设：这些RGS9基因变异会在RGS9-2细胞功能中产生改变。