Elucidating the Role of miRNA Dysregulation in Schizophrenia and Bipolar Disorder

阐明 miRNA 失调在精神分裂症和双相情感障碍中的作用

基本信息

批准号：
7268591
负责人：
Linda M Brzustowicz
金额：
$ 61.97万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-25 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268591
关键词：
Adult Affect Biological Biological Assay Biology Bipolar Disorder Brain Brain Diseases Candidate Disease Gene Cell Culture System Cell Cycle Cell Death Cell Proliferation Cell Survival Cell physiology Cells Class Classification Code Collection Cultured Cells DNA Resequencing Data Detection Development Disease Disease susceptibility Evaluation Gene Expression Gene Targeting Genes Genetic Genomics Genotype Grant Human In Situ Individual Knowledge Length Ligase Luciferases Mediating Mental disorders Messenger RNA Methods MicroRNAs Molecular Molecular Profiling Mus National Institute of Mental Health Neurons Neurotransmitters Numbers Pathogenesis Pathology Pattern Play Population Predisposition Primates Process Proteins Range Reaction Regulation Reporter Reproducibility Research Personnel Reverse Transcriptase Polymerase Chain Reaction Rodent Role Sampling Schizophrenia Site Staging Stretching System Testing Tissues Transfection Validation Variant base brain tissue cell type cost disorder risk genetic association insight interest novel novel therapeutics precursor cell pressure programs research study small molecule synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): microRNAs are powerful regulatory molecules that are abundantly expressed in the developing and adult mammalian brain. Many primate-specific microRNAs are now known, making this class of genes attractive candidates for involvement in brain disorders such as schizophrenia and bipolar affective disorder. Little is know about the pattern of expression of microRNAs in the brains of normally developing humans or individuals with these disorders. Multiple possible mechanisms exist through which microRNAs could play a role in disease. This project will utilize a variety of experimental approaches to increase our knowledge of the normal expression and function of microRNAs in the developing and adult brain, and investigate the possible role of microRNA in the susceptibility to schizophrenia and bipolar disorder. First, we will quantify microRNA expression in normal human brain tissue from several developmental stages as well as from a matched set of samples from individuals with schizophrenia, bipolar disorder, and psychiatrically normal controls (35 individuals from each group) to provide baseline knowledge about microRNA expression in the normally developing human brain and search for evidence that some microRNAs are improperly expressed in schizophrenia and/or bipolar disorder. Second, we will search for population variability in the sequences of microRNAs and their targets in mRNAs of interest in schizophrenia and bipolar disorder, as these may be functional variants that increase disease risk. Third, we will test these candidate variants, as well as tagSNPs from a limited number of microRNA clusters, for association to schizophrenia and bipolar disorder using trios from the NIMH Genetic Initiative collection. Fourth, we will develop a list of 12 microRNAs of greatest interest based on evidence of involvement in the biology of schizophrenia and bipolar disorder from the prior three steps, and use a cell culture/transfection system to manipulate microRNA expression and validate mRNA targets. Fifth, we will characterize the temporal and spatial expression of the 12 microRNAs of interest and select targets. Sixth, we will use a cell culture/transfection system to systematically characterize the cell biological consequences of alteration in microRNA expression on neuronal development and functioning. A better understanding of microRNA function in the normal and pathological state could provide novel insights into new therapeutic approaches for schizophrenia and bipolar disorder.

描述（由申请人提供）：microRNA 是强大的调节分子，在发育中和成年哺乳动物大脑中大量表达。目前，许多灵长类动物特异性的 microRNA 已为人所知，这使得此类基因成为参与精神分裂症和双相情感障碍等脑部疾病的有吸引力的候选基因。对于正常发育的人类或患有这些疾病的个体大脑中 microRNA 的表达模式知之甚少。 microRNA 在疾病中发挥作用存在多种可能的机制。该项目将利用多种实验方法来增加我们对发育中和成人大脑中 microRNA 的正常表达和功能的了解，并研究 microRNA 在精神分裂症和双相情感障碍易感性中的可能作用。首先，我们将量化几个发育阶段的正常人脑组织中的 microRNA 表达，以及来自精神分裂症、双相情感障碍和精神正常对照个体（每组 35 名个体）的一组匹配样本，以提供有关 microRNA 的基线知识正常发育的人脑中的表达，并寻找一些 microRNA 在精神分裂症和/或双相情感障碍中不正确表达的证据。其次，我们将寻找精神分裂症和双相情感障碍中 microRNA 序列及其目标 mRNA 的群体变异性，因为这些可能是增加疾病风险的功能变异。第三，我们将使用 NIMH 遗传计划集合中的三重奏来测试这些候选变体以及来自有限数量的 microRNA 簇的 tagSNP，以确定其与精神分裂症和双相情感障碍的关联。第四，我们将根据前三个步骤涉及精神分裂症和双相情感障碍生物学的证据，制定一份最感兴趣的 12 个 microRNA 列表，并使用细胞培养/转染系统来操纵 microRNA 表达并验证 mRNA 靶点。第五，我们将表征 12 种感兴趣的 microRNA 的时间和空间表达并选择目标。第六，我们将使用细胞培养/转染系统来系统地表征 microRNA 表达改变对神经元发育和功能的细胞生物学影响。更好地了解正常和病理状态下的 microRNA 功能可以为精神分裂症和双相情感障碍的新治疗方法提供新的见解。