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

基本信息

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
项目类别：
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

项目摘要

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）：尽管在识别涉及精神疾病的基因方面取得了长足的进步，但与这些疾病相关的遗传复杂性和表型变异性显着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型方法。我们拥有独特且非常强大的基于家庭的资源，其中包含大量已有的遗传和表型信息，我们可以从中构建与复杂疾病相关的分子途径，包括神经学起源。该项目将使用一种新型策略来定义microRNA在脑相关的内表型中的作用，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1,000名墨西哥裔美国人中识别并定量新颖和已知的microRNA。这些有效的基因表达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表型数据对广泛的神经解剖学和神经认知性状进行研究，以研究MicroRNA参与精神疾病的潜力。此外，我们将使用现有的全基因组基因型数据和转录曲线来研究microRNA对下游调节和下游调节的调节，从而对这些重要分子的遗传基础有重要理解。为了了解可能与精神疾病有关的miRNA，我们将对较小的人群进行类似的分析，这些人群由受双极I障碍，未受影响的兄弟姐妹和不相关控制的人组成。我们将开始使用功能分析的增益和丧失功能分析来探索异常miRNA表达的下游后果，以增强我们对miRNA生物学的理解。该项目的力量是确定与脑相关的内表型和精神病有关的遗传调节机制的力量。随着进步的技术和最近的科学发现，现在比以往任何时候都更强大的人类基因组的奥秘。我们的方法将结合几层遗传信息，以阐明精神疾病的分子病理及其内表型的分子病理，从而为发现这些使这些衰弱疾病的新型治疗和预防策略铺平了道路。公共卫生相关性：与精神疾病相关的死亡率和发病率很重要，并且遗传病因学得不到理解。在这个项目中，我们将采用一种新型策略来快速识别和量化大型基于家庭的队列中的新颖和已知的microRNA，而双相情感障碍会影响人群，以研究其在大脑结构和功能中的作用。这些有效的遗传调节剂的表征将极大地理解与精神疾病及其相关的末期型相关的分子病理学，并将为开发新的预防性措施和/或治疗铺平道路。