RGS Protein (2,4,9,10) Survey in Schizophrenia

精神分裂症中的 RGS 蛋白 (2,4,9,10) 调查

• 批准号: 6830303
• 负责人: Michael W Vogel
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830303
• 关键词: basal ganglia; biological signal transduction; cingulate gyrus; clinical research; dopamine; frontal lobe /cortex; human tissue; immunocytochemistry; in situ hybridization; neurochemistry; postmortem; protein localization; protein quantitation /detection; protein structure function; schizophrenia

DESCRIPTION (provided by applicant): RGS (Regulators-of-G-Protein-Signaling) proteins are a family of substances functionally related to G protein receptors and are located intracellularly near receptors. They function to terminate the action of agonist stimulation at a linked G protein-coupled receptor. These proteins have been described largely in animal brain and have not yet been fully characterized in human tissue. Evidence of their relevance to human brain diseases, especially to schizophrenia, is scant. Because schizophrenia is an illness responsive to dopamine receptor blockade, and possibly associated with augmented dopamine release, all parts of the dopamine system which participate in dopaminergic signal transduction deserve examination for potential association with pathophysiology. Moreover, RGS-4 (one of over 20 RGS proteins) has already been implicated in schizophrenia by microarray data and in situ hybridization in frontal cortex from one (but not from all) laboratories doing unbiased expression analysis in schizophrenia. Thus, based on a rational hypothesis and based on one piece of experimental data, relevant RGS proteins deserve a comprehensive survey in schizophrenia. If, after this analysis, we identify a signal in the schizophrenia cases, of abnormal quantities or distribution of any of these four RGS proteins, we will gear-up for a full characterization of the functional defect in the illness. We request funding in this small grant application for an initial screen of the four RGS proteins most closely related to dopamine, their regional densities in the normal and schizophrenia tissue and any differences from normal in either protein levels (by immunohistochemistry) or in protein expression (by in situ hybridization and Western analysis. Because of our previous work in schizophrenia neurochemistry, we have existing tissue blocks from schizophrenia (on treatment drugs), schizophrenia (off-drug x 6 mo), and matched control cases to use for this analysis. Thus, we can accomplish this experiment in a timely manner.

描述(由申请人提供)：RGS(G蛋白信号调节因子)蛋白是一类与G蛋白受体功能相关的物质，位于细胞内靠近受体的位置。它们的作用是终止G蛋白偶联受体上激动剂刺激的作用。这些蛋白质主要是在动物大脑中被描述的，在人类组织中还没有完全被描述。它们与人类大脑疾病，特别是与精神分裂症相关的证据很少。由于精神分裂症是一种对多巴胺受体阻断有反应的疾病，可能与多巴胺释放增加有关，因此参与多巴胺能信号转导的所有多巴胺系统部分都值得检查，以确定其与病理生理的潜在联系。此外，RGS-4(20多种RGS蛋白之一)已经通过微阵列数据和来自一个(但不是所有)实验室在精神分裂症中进行无偏见表达分析的额叶皮质的原位杂交数据而与精神分裂症有关。因此，基于理性假设和一项实验数据，相关RGS蛋白在精神分裂症中值得进行全面的调查。如果在这一分析之后，我们在精神分裂症病例中发现了这四种RGS蛋白中任何一种的异常数量或分布的信号，我们将准备全面描述疾病中的功能缺陷。我们要求在这一小额拨款申请中提供资金，用于初步筛选与多巴胺关系最密切的四种RGS蛋白，它们在正常组织和精神分裂症组织中的区域密度，以及在蛋白质水平(通过免疫组织化学)或蛋白质表达(通过原位杂交和Western分析)方面与正常组织的任何差异。由于我们之前在精神分裂症神经化学方面的工作，我们有来自精神分裂症(治疗药物)、精神分裂症(停药×6个月)和匹配的对照病例的现有组织块用于此分析。因此，我们可以及时完成这项实验。