RGS4 Polymorphisms and Neurobiology of Schizophrenia

RGS4 多态性与精神分裂症的神经生物学

• 批准号: 7107958
• 负责人: Konasale M Prasad
• 金额: $ 17.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-05 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107958
• 关键词: G protein; biological signal transduction; brain imaging /visualization /scanning; brain morphology; cerebral cortex; clinical research; gene expression; genetic polymorphism; human subject; magnetic resonance imaging; morphometry; neurobiology; patient oriented research; phenotype; schizophrenia

DESCRIPTION (provided by applicant): This Research Career Development plan proposes a program of training and research designed to clarify the in vivo biological impact of variations in the gene encoding regulator of G-protein signaling subtype 4 (RGS4) polymorphisms in schizophrenia patients, individuals at risk for schizophrenia and matched healthy subjects. Demonstrating an association between genetic variations and intermediate phenotypes provides an important additional support for genetic association. RGS4 underexpression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients is reported. Subsequently, an association of RGS4 gene with schizophrenia has been reported in 7 independently ascertained populations in USA, Europe, india and Brazil. Our preliminary studies showed smaller DLPFC in schizophrenia patients homozygous for allele T of SNP4 and allele A of SNP18 but not in healthy subjects suggesting an interaction with other illness related variables. According to the neurodevelopmental hypothesis of schizophrenia pathogenic process starts prior to the emergence of clinical symptoms. Therefore, studying cerebral changes in persons at genetically high risk for developing schizophrenia who have not yet manifested the illness could minimize the confounds due to the illness. Smaller DLPFC was also observed in schizophrenia subjects homozygous for Val allele of the COMT gene that has also been associated with schizophrenia. The proposed study plans to utilize structural MRI and phosphorus magnetic resonance spectroscopy to characterize the differences in morphometry and membrane chemical (phosphomonoesters and phosphodiesters) concentrations associated with RGS4 variations in these study groups. We will explore the associations of these imaging measures with COMT polymorphisms. Characterizing intermediate phenotypes using "cross-longitudinal" design helps in delineating longitudinal trajectory of cerebral correlates of genetic polymorphisms, designing novel medications and early detection.

描述（由申请人提供）：本研究职业发展计划提出了一项培训和研究计划，旨在阐明编码G-蛋白信号亚型4（RGS4）多态性的基因的体内生物学影响，对精神分裂症患者，精神分裂症和匹配健康受试者的风险和匹配的健康受试者的个体。证明遗传变异与中间表型之间的关联为遗传关联提供了重要的额外支持。据报道，精神分裂症患者背外侧前额叶皮层（DLPFC）的RGS4不渗透。随后，在美国，欧洲，印度和巴西的7个独立确定的人口中，已有7个独立确定的RGS4基因与精神分裂症的关联。我们的初步研究表明，在精神分裂症患者中，较小的DLPFC在SNP4和SNP18的等位基因A的纯合患者中，但在健康受试者中没有表明与其他疾病相关变量相互作用。根据临床症状出现之前，根据精神分裂症致病过程的神经发育假设。因此，研究尚未表现出疾病的精神分裂症患者处于遗传高风险的人的脑变化可以使由于疾病的混杂性最小化。还观察到较小的DLPFC在纯合子的精神分裂症受试者中，这也与精神分裂症有关的COMT基因的Val等位基因。拟议的研究计划利用结构MRI和磷磁共振光谱来表征这些研究组中与RGS4变化相关的形态计量学和膜化学（磷光植物和磷酸化的浓度）的差异。我们将探讨这些成像措施与COMT多态性的关联。使用“跨道义”设计表征中间表型有助于描述遗传多态性的脑相关性的纵向轨迹，设计新的药物和早期检测。