Elucidating the Role of miRNA Dysregulation in Schizophrenia and Bipolar Disorder

描述（申请人提供）：microRNAs是一种强大的调控分子，在发育和成年哺乳动物大脑中大量表达。许多灵长类动物特有的microrna现在已经被发现，这类基因成为与精神分裂症和双相情感障碍等脑部疾病有关的有吸引力的候选者。对于正常发育的人类或患有这些疾病的个体的大脑中microrna的表达模式知之甚少。microRNAs在疾病中发挥作用存在多种可能的机制。本项目将利用多种实验方法来增加我们对发育和成人大脑中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（每组35人）的一组匹配样本，以提供正常发育的人脑中microRNA表达的基线知识，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，我们将在精神分裂症和双相情感障碍中寻找microrna序列及其靶标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，我们将测试这些候选变体，以及来自有限数量的microRNA簇的标签snp，使用NIMH遗传倡议收集的三组样本来检测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中涉及精神分裂症和双相情感障碍生物学的证据，列出12个最感兴趣的microRNA，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个感兴趣的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后果。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。

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.