Identification of Novel MicroRNAs Associated with Brain Structure and Function

与大脑结构和功能相关的新型 MicroRNA 的鉴定

• 批准号: 8197695
• 负责人: Melanie Carless
• 金额: $ 51.42万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197695
• 关键词: Affect; Attention; Autistic Disorder; Biological Assay; Biology; Brain; Chromosome Mapping; Code; Complex; Comprehension; Data; Dementia; Development; Disease; Economic Burden; Extended Family; Family; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genome; Genomics; Genotype; Goals; Heritability; Human; Human Genome; Individual; Lymphocyte; MRI Scans; Magnetic Resonance Imaging; Measures; Mental Health; Mental disorders; Messenger RNA; Mexican Americans; MicroRNAs; Molecular; Molecular Analysis; Mood Disorders; Morbidity - disease rate; Neurobiology; Neurocognitive; Neurologic; Pathway interactions; Phenotype; Play; Population; Population Study; Prevention strategy; Proteins; Regulation; Regulator Genes; Resources; Role; Sampling; Schizophrenia; Severities; Siblings; Single Nucleotide Polymorphism; Small RNA; Structure; Technology; Therapeutic; Transcript; Variant; Work; base; cohort; cost effective; disorder risk; endophenotype; genetic resource; genome wide association study; genome-wide; genome-wide linkage; indexing; loss of function; lymphoblastoid cell line; meetings; member; molecular pathology; mortality; next generation; novel; novel strategies; novel therapeutics; public health relevance; trait

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.

描述（由申请人提供）：虽然在鉴定与精神疾病有关的基因方面已经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。我们拥有一个独特而强大的家族资源，其中包含大量预先存在的遗传和表型信息，我们可以在此基础上确定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定义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，我们将识别和定量来自大约40个家庭的1，000名墨西哥裔美国人中的新型和已知微小RNA。这些基因表达的有效调节剂可能会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microRNA参与精神疾病的可能性。此外，我们将使用现有的全基因组基因型数据和转录谱来研究microRNA的上游调节和下游调节，从而对这些重要分子的遗传基础有重要的了解。为了了解可能与精神疾病有关的miRNAs，我们将在一个较小的人群中进行类似的分析，该人群由双相I型障碍患者、未受影响的兄弟姐妹和无关对照组成。我们将开始使用功能获得和丧失分析来探索异常miRNA表达的下游后果，以加强我们对miRNA生物学的理解。这个项目的力量，以确定机制的基因调控涉及脑相关的内在表型和精神疾病是前所未有的。随着技术的进步和最近的科学发现，解开人类基因组之谜的潜力比以往任何时候都要强大。我们的方法将联合收割机几层遗传信息来阐明精神疾病及其内在表型的分子病理学，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。 公共卫生相关性：与精神疾病相关的死亡率和发病率是显著的，并且遗传病因学知之甚少。在这个项目中，我们将采用一种新的策略来快速识别和定量一个大型的基于家庭的队列和一个双相I型障碍影响的队列中的新的和已知的microRNA，以研究它们在大脑结构和功能中的作用。这些有效的遗传调节因子的表征将极大地有助于理解与精神疾病及其相关内在表型相关的分子病理学，并为开发新的预防措施和/或疗法铺平道路。