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Epigenetics of Obesity and Insulin Resistance

肥胖和胰岛素抵抗的表观遗传学

基本信息

批准号：
8428561
负责人：
JANE KIM
金额：
$ 7.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8428561
关键词：
Accounting Adipose tissue Adolescent Adult Age Attention Basic Science Bioinformatics Blood Vessels C57BL/6 Mouse C57BL/6N Mouse Cardiovascular Diseases Cells ChIP-seq Childhood Collaborations Computer Analysis DNA Methylation Data Development Diet Disease Elements Endocrinologist Environment Environmental Risk Factor Epigenetic Process Exhibits Faculty Fatty acid glycerol esters Folic Acid Funding Future Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Genetic Transcription Goals Histocompatibility Testing Histones Inbreeding Insulin Insulin Receptor Insulin Resistance Lateral Left Liver Lobe Longevity Matched Group Mentors Metabolic Metabolic Diseases Metabolism Methylation Modeling Modification Molecular Molecular Profiling Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Overnutrition Pattern Peroxisome Proliferator-Activated Receptors Phenotype Population Predisposition Prevalence Promoter Regions Publishing RNA Regulation Research Risk Factors Rodent Scientist Stroke Subgroup Surveys Techniques Testing Tissue Banking Tissue Banks Tissues Training Transcriptional Regulation United States United States National Institutes of Health Variant Visceral Work blood glucose regulation chromatin immunoprecipitation design epigenetic variation epigenome feeding genome wide association study genome-wide glucose metabolism histone modification in utero in vivo lipid biosynthesis lipid metabolism male new technology novel strategies nutrition obesity in children offspring postnatal prenatal prevent promoter public health relevance research study response subcutaneous transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The goals of this proposal are two-fold: (i) to investigate epigenetic regulation of transcription in insulin target tissues in obesity and (ii) to generate a platform for future R01 funding. The PI is an NIH-trained pediatric endocrinologist skilled in basic science research, currently on faculty at UCSD. Obesity and insulin resistance are major risk factors to the development of type 2 diabetes, cardiovascular disease, and stroke. These metabolic diseases are associated with profound alterations in gene expression caused by both genetic and environmental factors. Epigenetics provides a mechanism by which environmental factors modify gene expression and the predisposition to disease at all ages. Epigenetic mechanisms of gene regulation include DNA methylation and histone modifications. Highly inbred rodent strains such as C57BL/6 mice are nearly genetically identical. Yet these strains show substantial variation in longevity, adiposity, and insulin resistance. Epigenetic variation is a likely factor to account for this high phenotypic variability. In this proposal, we exploit the wide metabolic variation in high- fat diet (HFD)-fed C57BL/6 male mice as a means to investigate how epigenetic modifications regulate transcriptional control in obesity and insulin resistance. In order to achieve this goal, we will apply high throughput techniques (ChIP-Seq and RNA-Seq) to survey global epigenetic histone modification and transcriptome profiles in adipose and liver tissue of C57BL/6 mice. We hypothesize that i) HFD alters histone modification patterns in liver and adipose tissues (Aim 1), and ii) that epigenetic differences account for the wide variation in insulin resistance following HFD (Aim 2). In Aim 1, we will compare tissues collected from age-matched mice fed either HFD or standard chow. In Aim 2, we will surgically remove and bank tissues from young mice, place all mice on HFD, and perform metabolic testing to define 2 distinct subgroups of mice with either severe or mild insulin resistance. We will then analyze tissues collected at study initiation, comparing differences between both phenotypic groups. In both aims, tissues will be subjected to ChIP-Seq analysis to determine histone methylation patterns that mark active promoter and repressor elements (namely H3K4me3 and H3K27me3). These data will be integrated with gene expression profiles obtained by RNA-Seq. This work will be conducted in collaboration with Dr. Bing Ren at UCSD, a well-recognized expert in high throughput techniques and computational analysis. Dr. Ren's lab will perform all sequencing and assist with bioinformatics analysis. The in vivo experiments will be conducted in the lab of my K08 mentor, Dr. Jerrold Olefsky. This approach is designed to draw on my strengths as a bench scientist and pediatric endocrinologist, providing an independent focus of research and platform for future R01 funding.

描述（由申请人提供）：本提案的目标有两个：(i)研究肥胖症中胰岛素靶组织的转录表观遗传调控；（ii）研究胰岛素靶组织的转录表观遗传调控