Elucidating the Role of miRNA Dysregulation in Schizophrenia and Bipolar Disorder

描述(申请人提供)：microRNAs是一种强大的调节分子，在发育中的和成年哺乳动物的大脑中大量表达。许多灵长类动物特有的microRNA现在已经被发现，这使得这类基因对于参与精神分裂症和双相情感障碍等大脑疾病的候选基因很有吸引力。对于正常发育的人类或患有这些疾病的人的大脑中microRNAs的表达模式，人们知之甚少。存在多种可能的机制，通过这些机制，microRNAs可以在疾病中发挥作用。这个项目将利用各种实验方法来增加我们对microRNAs在发育中和成人大脑中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的一组匹配样本(每组35人)，以提供关于正常发育人脑中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适当表达的证据。其次，我们将在精神分裂症和双相情感障碍感兴趣的mRNAs中寻找microRNAs序列及其靶标的群体变异性，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异，以及来自有限数量的microRNA簇的标签SNPs，使用NIMH遗传倡议收集的三个SNP来测试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参与精神分裂症和双相情感障碍生物学的证据，开发出一份最感兴趣的12个microRNA的清单，并使用细胞培养/转基因系统来操纵microRNA的表达和验证mRNA靶标。第五，我们将表征12个感兴趣的microRNAs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microRNA在正常和病理状态下的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.