Identification of Novel MicroRNAs Associated with Brain Structure and Function

描述（由申请人提供）：尽管在识别与精神疾病相关的基因方面取得了相当大的进展，但与这些疾病相关的遗传复杂性和表型变异性极大地阻碍了我们对这些疾病的理解。使用内表型作为疾病风险的指标是探索与精神疾病相关的遗传决定因素的一种新方法。我们有一个独特而强大的基于家庭的资源，其中包含大量预先存在的遗传和表型信息，我们可以根据这些信息来定义与复杂疾病相关的分子途径，包括神经系统疾病。该项目将使用一种新的策略来确定microrna在脑相关内表型中的作用，从而有助于阐明精神疾病发展的机制。使用最先进的技术，我们将在大约40个家庭的1000名墨西哥裔美国人中鉴定和定量新的和已知的microrna。这些基因表达的有效调节因子可能影响与神经生物学相关的多种遗传途径。我们将使用先前收集的广泛的神经解剖学和神经认知特征的表型数据来研究microrna参与精神疾病的可能性。此外，我们将利用现有的全基因组基因型数据和转录谱来研究microrna对上游和下游的调节，从而获得对这些重要分子的遗传基础的重要理解。为了了解可能与精神疾病有关的mirna，我们将在一个较小的人群中进行类似的分析，该人群包括患有双相I型障碍的个体、未受影响的兄弟姐妹和不相关的对照组。我们将开始探索异常miRNA表达的下游后果使用增益和损失的功能分析，以加强我们对miRNA生物学的理解。这个项目在确定与大脑相关的内表型和精神疾病有关的基因调控机制方面的力量是前所未有的。随着先进的技术和最新的科学发现，解开人类基因组之谜的潜力比以往任何时候都更大。我们的方法将结合多层遗传信息来阐明精神疾病的分子病理学及其内表型，从而为发现这些使人衰弱的疾病的新的治疗和预防策略铺平道路。

DESCRIPTION (provided by applicant): Although considerable advances have been made in identifying genes involved in psychiatric disease, the genetic complexity and phenotypic variability associated with these disorders significantly hinders our comprehension of these illnesses. The use of endophenotypes as indices of disease risk is a novel way to explore the genetic determinants associated with psychiatric disorders. We have a unique and very powerful family-based resource, which contains a vast array of pre-existing genetic and phenotypic information from which we can build on to define molecular pathways associated with complex diseases, including those of neurological origin. This project will use a novel strategy to define a role for microRNAs in brain-related endophenotypes and thus help to elucidate the mechanisms by which psychiatric disorders develop. Using state-of-the-art technologies we will identify and quantitate novel and known microRNAs in 1,000 Mexican Americans from approximately 40 families. These potent regulators of gene expression are likely to influence multiple genetic pathways associated with neurobiology. We will use previously collected phenotypic data on a wide range of neuroanatomical and neurocognitive traits to investigate the potential for involvement of microRNAs in psychiatric disorders. Further, we will use existing whole-genome genotypic data and transcriptional profiles to investigate upstream modulation of and downstream regulation by microRNAs, thereby gaining an important understanding of the genetic basis of these important molecules. To gain an understanding of miRNAs that might be implicated in a psychiatric disorder, we will perform similar analyses in a smaller population consisting of individuals affected with bipolar I disorder, unaffected siblings and unrelated controls. We will begin to explore the downstream consequences of aberrant miRNA expression using gain and loss of function analyses to strengthen our understanding of miRNA biology. The power of this project to identify mechanisms for genetic regulation involved in brain-related endophenotypes and psychiatric disease is unprecedented. With advancing technologies and recent scientific discoveries the potential to unravel the mysteries of the human genome is now stronger than ever. Our approach will combine several layers of genetic information to elucidate the molecular pathology of psychiatric diseases and their endophenotypes, thereby paving the way for the discovery of novel therapeutic and prevention strategies for these debilitating illnesses.