Imaging the Impact of Glutamate Liability Genes in Schizophrenia

谷氨酸责任基因对精神分裂症的影响成像

基本信息

批准号：
7470504
负责人：
ANGUS W MACDONALD
金额：
$ 29.9万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-08 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7470504
关键词：
Address Adult Alleles Animals Behavioral Biological Blood specimen Brain Build-it COMT gene Candidate Disease Gene Catechol O-Methyltransferase Characteristics Cognitive DNA Diagnosis Disease Dopamine Environment Etiology Expectancy Exploratory/Developmental Grant Family Study Functional Magnetic Resonance Imaging Functional disorder Funding General Population Genes Genetic Genetic Polymorphism Genomics Genotype Glutamates Health behavior Image Individual Differences Lead MRI Scans Magnetic Resonance Imaging Measures Medical center Molecular Genetics Mutation NRG1 gene Neuregulin 1 Numbers PLAB Protein PPP3CC gene Patients Pattern Performance Phenotype Population Prefrontal Cortex Process Psychotic Disorders Public Health Registries Relative (related person)Research Risk Risk Factors Role Sampling Savings Schizophrenia Science Screening procedure Staging Stratification Symptoms Techniques Testing Thinking Work base cost design endophenotype epsin falls gene discovery human PPP3CC protein insight neuromechanism programs relating to nervous system theories

项目摘要

DESCRIPTION (provided by applicant): To reveal the effects of candidate genes on brain function in schizophrenia, we will employ a two-stage screening process to test genes for association with context processing deficits and prefrontal cortical dysfunction. Using an endophenotype-driven approach, we will determine whether mutations in glutamatergic genes underpin neural and cognitive risk for schizophrenia. 1) The first stage will test whether five glutamate moderating genes (RGS4, DTNBP1, GRM3, NRG1, and DAOA) are associated with individual differences in context processing in a large general population sample. We will also use resampling techniques to explore whether seven less established glutamate moderating genes (GRIA2, EPSIN 4, PPP3CC, GRIN, DAO, PRODH and YWHAH) contribute to context processing, and whether glutamate polymorphisms interact with the schizophrenia risk allele of COMT. 2) The second stage will evaluate whether glutamate modulating genes associated with context processing in the general population are related to context processing deficits in schizophrenia patients and their biological relatives. 3) Finally, to understand the relationship between glutamate polymorphisms and brain dysfunction, we will use functional magnetic resonance imaging (fMRI) to examine prefrontal cortical activity in healthy relatives of schizophrenia patients and controls during performance of a context processing task. This project falls within the scope of the R21 mechanism because studies in the general population and schizophrenia are established and funded. R21 funding will support behavioral phenotyping and genotyping, but not fMRI scanning, recruitment, or additional blood sampling costs. The current study has the potential to confirm the importance of glutamate modulating genes in the etiology of schizophrenia and highlight the intermediate mechanisms through which these genes lead to disease manifestation. PUBLIC HEALTH RELEVANCE: To reveal the effects of candidate genes on brain function in schizophrenia, we will employ a two-stage screening process to test genes for association with context processing deficits and prefrontal cortical dysfunction. The first stage will test whether glutamate moderating genes are associated with individual differences in context processing in a large general population registry. The second stage will evaluate whether positively screened glutamate genes are related to context processing deficits in schizophrenia patients and their biological relatives, and determine whether these genes are related to fMRI measures of brain function in relatives and controls.

描述（由申请人提供）：为了揭示候选基因对精神分裂症脑功能的影响，我们将采用两阶段筛选过程来测试基因与上下文处理缺陷和前额叶皮质功能障碍相关。我们将采用跨表型驱动的方法来确定谷氨酸能基因的突变是否是精神分裂症的神经和认知风险的基础。 1）第一阶段将测试五个谷氨酸调节基因（RGS4，DTNBP1，GRM3，NRG1和DAOA）是否与大型一般人群样本中上下文处理中的个体差异有关。我们还将使用重采样技术来探索七个较少建立的谷氨酸调节基因（Gria2，Epsin 4，Ppp3cc，grin，dao，podh和ywhah）是否有助于上下文处理，以及谷氨酸多态性是否与Comt的精神分裂症风险相互作用。 2）第二阶段将评估谷氨酸调节基因是否与普通人群的上下文处理相关的基因是否与精神分裂症患者及其生物亲属的上下文处理缺陷有关。 3）最后，为了了解谷氨酸多态性和脑功能障碍之间的关系，我们将使用功能性磁共振成像（fMRI）检查精神分裂症患者健康亲属的前额叶皮质活性以及在上下文处理任务执行过程中对照组的对照。该项目属于R21机制的范围，因为对普通人群和精神分裂症的研究得到了建立和资助。 R21资金将支持行为表型和基因分型，但不能支持fMRI扫描，招募或额外的血液采样成本。当前的研究有可能证实谷氨酸调节基因在精神分裂症病因中的重要性，并强调了这些基因导致疾病表现的中间机制。公共卫生相关性：为了揭示候选基因对精神分裂症中脑功能的影响，我们将采用两阶段筛查过程来测试基因与上下文处理缺陷和前额叶皮质功能障碍的关联。第一阶段将测试谷氨酸调节基因是否与大型一般人群注册中的上下文处理中的个体差异有关。第二阶段将评估精神分裂症患者及其生物学亲戚的上下文处理缺陷是否与上下文处理缺陷有关，并确定这些基因是否与亲属和对照组中脑功能的fMRI测量有关。