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有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显著阻碍了我们对这些疾病的理解。使用内表型作为疾病风险指数是探索与精神疾病相关的遗传决定因素的一种新方法。我们拥有独特和非常强大的以家庭为基础的资源，其中包含大量先前存在的遗传和表型信息，我们可以根据这些信息来确定与复杂疾病相关的分子途径，包括神经起源的疾病。该项目将使用一种新的策略来定义microRNAs在与脑相关的内表型中的作用，从而有助于阐明精神障碍发展的机制。使用最先进的技术，我们将在来自大约40个家庭的1000名墨西哥裔美国人中识别和量化新的和已知的microRNA。这些强大的基因表达调节器可能会影响与神经生物学相关的多条遗传途径。我们将使用之前收集的关于广泛的神经解剖学和神经认知特征的表型数据来研究microRNAs参与精神障碍的可能性。此外，我们将利用现有的全基因组基因数据和转录图谱来研究microRNAs对上游和下游的调控，从而对这些重要分子的遗传学基础有一个重要的了解。为了了解可能与精神障碍有关的miRNAs，我们将在一个较小的人群中进行类似的分析，该人群由受双相I型障碍影响的个人、未受影响的兄弟姐妹和无关的对照组成。我们将开始使用得失功能分析来探索miRNA异常表达的下游后果，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相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，揭开人类基因组之谜的可能性现在比以往任何时候都更强。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，从而为发现这些令人衰弱的疾病的新治疗和预防策略铺平道路。 公共卫生相关性：与精神疾病相关的死亡率和发病率很高，而遗传病因知之甚少。在这个项目中，我们将采用一种新的策略，在一个大型的基于家族的队列和一个受双相情感障碍影响的队列中，快速识别和定量新的和已知的microRNAs，以研究它们在大脑结构和功能中的作用。这些强大的基因调控因子的特征将极大地有助于理解与精神疾病相关的分子病理学及其相关的内表型，并将为开发新的预防措施和/或治疗方法铺平道路。

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. PUBLIC HEALTH RELEVANCE: Mortality and morbidity rates associated with psychiatric disorders are significant and the genetic etiology is poorly understood. In this project we will employ a novel strategy to rapidly identify and quantitate novel and known microRNAs in a large family-based cohort and a bipolar I disorder affected cohort to investigate their role in brain structure and function. Characterization of these potent genetic regulators will contribute immensely to the understanding of the molecular pathology associated with psychiatric disorders and their related endophenotypes and will pave the way for the development of new preventative measures and/or therapies.