Function and specificity of thiazolinedione induced eRNAs

噻唑啉二酮诱导的 eRNA 的功能和特异性

基本信息

批准号：
8522942
负责人：
Jill M. Marinis
金额：
$ 4.71万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8522942
关键词：
2,4-thiazolidinedione Address Adipocytes Adverse effects Affect Antidiabetic Drugs Behavior Binding Caring Cells ChIP-seq Characteristics Clinical Code Complement Data Data Set Detection Diabetes Mellitus Drug Targeting Enhancers Environment Epigenetic Process Exposure to Functional RNA Gene Expression Genes Genetic Genetic Transcription Glucose Goals Individual Insulin Insulin Resistance Knowledge Lead Life Light Mediating Metabolic Metabolism Microarray Analysis Molecular Molecular Mechanisms of Action Molecular Profiling Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nuclear Hormone Receptors Nuclear Receptors PPAR gamma Pharmaceutical Preparations Physiological Population Proteins RNA Recording of previous events Research Research Proposals Role Running Safety Signal Transduction Site Specificity Techniques Testing Therapeutic Thiazolidinediones Training Transcript Translating Triglycerides career cell type chromatin immunoprecipitation diabetic functional genomics genome-wide histone modification improved insight insulin sensitivity lipid biosynthesis macrophage mammalian genome next generation sequencing novel novel strategies overexpression public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR?) is a master regulator of adipogenesis and metabolism. The widely used anti-diabetic class of thiazolinedione (TZD) drugs target PPAR? to decrease circulating levels of glucose, insulin, triglycerides, and free fatty acids; however, te molecular mechanisms and cell targets of these actions are not completely understood. We have employed a novel genome-wide technique, Global Run-On Sequencing (GRO-seq) to identify TZD-induced long non- coding RNAs (lncRNA) from PPAR? bound enhancers, (eRNAs), in adipocytes. We hypothesize that eRNAs mediate PPAR? expression profiles in adipocytes and dictate cell-specific TZD-induced gene expression networks. The first aim of this proposal is dedicated to determining the physiological significance and mechanism of action of eRNAs in adipocytes. Both global and individual functions of eRNAs will be tested in experiments using RNAse or eRNA knockdown and overexpression. The second aim uses GRO-seq to identify eRNAs in macrophages. GRO-seq datasets of adipocytes and macrophages will be compared to identify cell type specific eRNAs. Identification of novel adipocyte specific factors and understanding their mechanism of action has the potential of tailoring therapeutics for cell specific actions to minimize adverse side-effects of TZDs.

描述（由申请人提供）：核激素受体过氧化物酶体增殖物激活受体γ（PPAR？）是脂肪生成和代谢的主要调节剂。广泛使用的抗糖尿病类噻唑啉二酮 (TZD) 药物以 PPAR?降低葡萄糖、胰岛素、甘油三酯和游离脂肪酸的循环水平；然而，这些作用的分子机制和细胞靶点尚未完全了解。我们采用了一种新颖的全基因组技术，即全局连续测序 (GRO-seq)，从 PPAR? 中识别 TZD 诱导的长非编码 RNA (lncRNA)？脂肪细胞中的结合增强子（eRNA）。我们假设 eRNA 介导 PPAR？脂肪细胞中的表达谱并决定细胞特异性 TZD 诱导的基因表达网络。该提案的第一个目标是致力于确定 eRNA 在脂肪细胞中的生理意义和作用机制。 eRNA 的整体和个体功能都将在实验中使用 RNAse 或 eRNA 敲低和过表达进行测试。第二个目标是使用 GRO-seq 来识别巨噬细胞中的 eRNA。将比较脂肪细胞和巨噬细胞的 GRO-seq 数据集，以确定细胞类型特异性 eRNA。鉴定新的脂肪细胞特异性因子并了解其作用机制有可能针对细胞特异性作用定制治疗方法，以最大限度地减少 TZD 的不良副作用。