Obesity Brain Expression

肥胖大脑表达

• 批准号: 8757711
• 负责人: ANITA L DESTEFANO
• 金额: $ 68.66万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-29 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757711
• 关键词: Aging; Base of the Brain; Binding; Biological; Body mass index; Brain; Brain Part; Brain region; Cessation of life; Clinical; Code; Cohort Studies; Collaborations; Complex; Corpus striatum structure; DNA Sequence; Data; Databases; Diabetes Mellitus; Disease; Endoribonucleases; Energy Metabolism; Etiology; Exons; Framingham Heart Study; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Hepatitis C virus; Human; Hypothalamic structure; Individual; Investigation; Investments; Lateral; Length; Life; Liver; Longevity; Measures; Memory; Messenger RNA; Methods; MicroRNAs; Molecular Profiling; Neurosecretory Systems; Non obese; Nucleotides; Obesity; Participant; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase I Clinical Trials; Phenotype; Process; Protein Isoforms; RNA; RNA Sequences; RNA Splicing; RNA analysis; Religion and Spirituality; Resources; Role; Sampling; Technology; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; Transcript; Translations; Variant; Virus Replication; Waist-Hip Ratio; Weight; base; brain tissue; cohort; design; endoribonuclease; exome; exome sequencing; genetic variant; genome wide association study; genome-wide; human DICER1 protein; insight; next generation; next generation sequencing; novel; programs; prospective; public health relevance; risk variant; transcriptome sequencing; transcriptomics

DESCRIPTION (provided by applicant): Neuroendocrine factors have been convincingly implicated in the etiology of obesity. Although genome-wide association studies (GWAS), have identified scores of genes and loci associated with obesity, insight into the functional roles for these genes, particularly within the human brain, is lacking. Many brain banks do not have a single body mass index (BMI) measure. However, brain donation programs within longitudinal, cohort studies represent a unique resource of brain samples with up to six decades of ante-mortem data including BMI. This proposal is a collaboration among three such longitudinal cohort studies: 1) The Framingham Heart Study (FHS) 2) The Religious Order Study (ROS) and 3) the Memory and Aging Project (MAP). Selection from over 1,300 post mortem brain samples already donated via these studies enabled identification of 75 samples from consistently obese individuals and 75 samples from individuals with consistently normal BMI (18.5<BMI<25). These carefully selected samples provide an unprecedented opportunity to study the relationship of gene expression in specific brain regions to BMI providing key insight into the neuroendocrine control of BMI. This application proposes to apply next generation RNA sequencing and microRNA sequencing technology and state of the art statistical approaches in highly characterized, selected samples from the FHS, ROS and MAP brain banks to further the understanding of the genetic basis of obesity. The return on investment in generating these data will be maximized by creating a publicly available resource of extensive brain derived genomic data of value for studying a wide range of diseases and clinical measures. In Aim 1 we propose RNA and microRNA sequencing in 2 brain regions: lateral hypothalamus and striatum to determine region specific gene expression patterns in 75 samples from consistently obese individuals and 75 controls (consistently normal BMI). RNA-sequencing will identify coding sequence variants, novel gene transcripts, & splice junctions and estimate brain region specific RNA expression levels for individual exons of genes. MicroRNA sequencing will identify short RNA sequences implicated in regulation of gene expression. We will use these data to characterize genes previously identified in genomewide association studies and to identify novel genes differentially expressed between brain tissue from obese and non-obese individuals. In Aim 2 we will integrate the genome-wide SNP and transcriptome data to perform eSNP, eQTL, and pathway analyses to identify underlying biological mechanisms. These studies will provide insight into the role of genes in the initiation and pathophysiology of obesity and create a valuable public database containing comprehensively characterized regional gene expression in brain in a cohort of comprehensively phenotypically characterized participants.

描述（由申请人提供）：神经内分泌因素已令人信服地涉及肥胖病因。尽管全基因组关联研究（GWAS）已经鉴定出与肥胖相关的基因和基因座的评分，但缺乏对这些基因的功能作用，尤其是人脑内部的功能作用的见解。许多脑库没有单个体重指数（BMI）度量。但是，纵向研究中的大脑捐赠计划代表了大脑样本的独特资源，其中包括BMI在内的六十年的尸体数据。该建议是三项这样的纵向队列研究中的合作：1）弗雷明汉心脏研究（FHS）2）宗教秩序研究（ROS）和3）记忆和老化项目（地图）。已经通过这些研究捐赠的1,300多个尸体大脑样本的选择可以鉴定出始终肥胖个体的75个样本和来自BMI始终正常的个体的75个样本（18.5 <bmi <25）。这些精心选择的样品提供了一个前所未有的机会，可以研究特定大脑区域中基因表达与BMI的关系，从而为BMI的神经内分泌控制提供了关键的见解。该应用程序建议在高度特征的FHS，ROS和MAP Brain Banks中应用下一代RNA测序和MicroRNA测序技术以及艺术统计方法的状态，以进一步了解肥胖的遗传基础。通过创建广泛的大脑衍生基因组数据的公开资源来研究广泛的疾病和临床措施，可以最大程度地提高产生这些数据的投资回报。在AIM 1中，我们提出了2个大脑区域中的RNA和microRNA测序：下丘脑和纹状体，以确定来自始终肥胖个体和75个对照的75个样品中区域特定基因表达模式（始终是正常的BMI）。 RNA测序将确定编码序列变体，新型基因转录和剪接连接和估计基因外显子的大脑区域特异性RNA表达水平。 microRNA测序将确定与基因表达调节有关的短RNA序列。我们将使用这些数据来表征先前在全基因组关联研究中鉴定出的基因，并鉴定肥胖和非肥胖个体之间脑组织之间差异表达的新基因。在AIM 2中，我们将整合全基因组SNP和转录组数据以执行ESNP，EQTL和途径分析以识别潜在的生物学机制。这些研究将洞悉基因在肥胖的起始和病理生理学中的作用，并创建一个有价值的公共数据库，该数据库包含大脑在大脑中全面表征的区域基因表达中，在一系列全面的表型特征参与者中。