Molecular Genetics and Gene Expression in Psychiatric Disorders

精神疾病的分子遗传学和基因表达

• 批准号: 7256821
• 负责人: RUTH KOHEN
• 金额: $ 17.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-10 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256821
• 关键词: Affect; Animal Model; Autopsy; Behavior; Biotin; Bipolar Disorder; Brain; Brain region; Cells; Cerebrospinal Fluid; Chronic Disease; Complex; Data; Development; Disease; Disruption; Environmental Risk Factor; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Haplotypes; Harvest; Hippocampus (Brain); Homeostasis; Human; Investigation; Label; Lead; Life; Major Depressive Disorder; Medical; Mental Depression; Mental disorders; Mentally Ill Persons; Minisatellite Repeats; Modeling; Molecular Genetics; Molecular Profiling; Nucleic Acid Regulatory Sequences; Oligonucleotide Microarrays; Parahippocampal Gyrus; Pathway Analysis; Patients; Pattern; Phenotype; Polymerase Chain Reaction; Population; Productivity; Public Health; RNA; Regulator Genes; Regulatory Element; Research; Research Institute; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Schizophrenia; Serotonin; Staging; System; Testing; Time; Treatment Cost; Universities; Washington; brain tissue; burden of illness; dentate gyrus; disorder risk; environmental stressor; gene environment interaction; gene interaction; genetic association; genetic risk factor; granule cell; laser capture microdissection; member; neuropathology; novel; serotonin transporter

DESCRIPTION (provided by applicant): Major psychiatric illnesses such as schizophrenia, bipolar disorder and depression are complex diseases caused by the interaction of genetic and environmental factors. These influences intersect at the level of gene expression and create complex phenotypes that are the result of collective influences by groups of genes acting in concert across different brain regions. This study will investigate the dentate gyrus (DG) of the hippocampus and use large-scale gene expression profiling to model the regulatory relationships between genes in nearly homogeneous populations of DG granule cells. We hypothesize that disruption in the serotonin system by genetic polymorphisms of the serotonin transporter (SERT) gene results in alterations in gene expression in the dentate gyrus (DG) of the hippocampus which contribute to psychiatric disorders. We will compare gene regulatory networks in the DG in postmortem brain tissue from healthy and mentally ill subjects, and in mentally healthy carriers of different SERT haplotypes. This will allow us to test the hypothesis that certain SERT polymorphisms can raise the risk for mental illness by interfering with local patterns of gene expression. Homogeneous cell populations of dentate gyrus granule cells from mid-hippocampus will be harvested using laser capture microdissection, aRNA amplification, and hybridization to Affymetrix oligonucleotide microarrays. Gene expression profiles will be used to create models of gene regulatory networks in the DG. These models will allow us to make predictions about key regulatory elements in the DG gene network, and these predictions will be tested by quantitative RT-PCR. Relevance of this research to public health: Major psychiatric illnesses are chronic diseases that carry a very heavy disease burden both in terms of human suffering and as financial losses due to treatment costs and lost productivity. Previous genetic association studies have shown that allelic variants of SERT can influence disease risk in combination with environmental factors. In this study we will compare gene expression between groups of subjects with major psychiatric illnesses and normal controls, model the interaction of genes in a gene regulatory network, and identify key regulatory elements where genetic and environmental influences can intersect. This will increase our understanding of genetic risk factors for mental illness, gene-environment interactions, and highlight possible new treatment strategies.

描述（申请人提供）：精神分裂症、躁郁症、抑郁症等主要精神疾病是遗传因素和环境因素相互作用引起的复杂疾病。 这些影响在基因表达水平上交叉，并产生复杂的表型，这是不同大脑区域协同作用的基因组集体影响的结果。 本研究将研究海马齿状回 (DG)，并使用大规模基因表达谱来模拟几乎同质的 DG 颗粒细胞群体中基因之间的调控关系。 我们假设血清素转运蛋白（SERT）基因的遗传多态性对血清素系统的破坏导致海马齿状回（DG）基因表达的改变，从而导致精神疾病。 我们将比较健康和精神病受试者死后脑组织以及不同 SERT 单倍型的精神健康携带者 DG 中的基因调控网络。 这将使我们能够检验以下假设：某些 SERT 多态性可以通过干扰基因表达的局部模式来增加患精神疾病的风险。 将使用激光捕获显微切割、aRNA 扩增以及与 Affymetrix 寡核苷酸微阵列杂交来收获来自海马中部的齿状回颗粒细胞的同质细胞群。 基因表达谱将用于在 DG 中创建基因调控网络模型。 这些模型将使我们能够对 DG 基因网络中的关键调控元件进行预测，并且这些预测将通过定量 RT-PCR 进行测试。 这项研究与公共卫生的相关性：主要精神疾病是慢性疾病，在人类痛苦方面以及由于治疗费用和生产力损失造成的经济损失方面都带来非常沉重的疾病负担。 先前的遗传关联研究表明，SERT 的等位基因变异可以与环境因素结合影响疾病风险。 在这项研究中，我们将比较患有主要精神疾病的受试者组和正常对照组之间的基因表达，模拟基因调控网络中基因的相互作用，并确定遗传和环境影响可能交叉的关键调控元件。 这将增加我们对精神疾病遗传风险因素、基因与环境相互作用的理解，并强调可能的新治疗策略。