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: 7793384
• 负责人: RUTH KOHEN
• 金额: $ 17.43万
• 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/7793384
• 关键词: Affect; Animal Model; Autopsy; Behavior; Biotin; Bipolar Disorder; Brain; Brain region; Cells; Cerebrospinal Fluid; Chronic Disease; Complex; Data; Development; Disease; 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 Research; 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; 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; treatment strategy

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、双相情感障碍和抑郁症等主要精神疾病是由遗传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相交，并创造出复杂的表型，这些表型是跨不同大脑区域的一组基因共同作用的结果。这项研究将研究海马齿状回(DG)，并使用大规模的基因表达谱来模拟DG颗粒细胞几乎相同群体中基因之间的调控关系。我们假设，5-羟色胺转运体(SERT)基因的遗传多态性破坏了5-羟色胺系统，导致了海马齿状回(DG)基因表达的变化，从而导致了精神障碍。我们将比较健康人和精神病患者以及不同SERT单倍型精神健康携带者死后脑组织DG中的基因调控网络。这将使我们能够检验这样的假设，即某些SERT多态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。通过激光捕获显微切割、Arna扩增和与Affymetrix寡核苷酸微阵列杂交，将从海马区中部获取均一的齿状回颗粒细胞群。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做出预测，这些预测将通过定量RT-PCR进行验证。这项研究与公共卫生的相关性：重大精神疾病是一种慢性病，它给人类带来非常沉重的疾病负担，也是由于治疗费用和生产力丧失造成的经济损失。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一起影响疾病风险。在这项研究中，我们将比较患有严重精神疾病的受试者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的遗传风险因素、基因-环境相互作用的理解，并突出可能的新治疗策略。