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Transcriptional Mechanisms of Human Insulin Resistance

人类胰岛素抵抗的转录机制

基本信息

批准号：
10088438
负责人：
Evan D Rosen
金额：
$ 64.05万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088438
关键词：
ATAC-seq Address Adipocytes Affect Alleles Allelic Imbalance Area Atlases Automobile Driving Binding Biological Assay CRISPR interference Chromatin Complement Complex Computer Models DNA Binding Data Data Set Development Discipline Disease Elements Enhancers Funding Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genetic Variation Goals Health Hi-C Human Human Genetics Human Genome In Vitro Individual Insulin Insulin Resistance Knock-out Lead Link Maps Metabolic Modeling Molecular Molecular and Cellular Biology Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Pathogenesis Pathway interactions Peripheral Physiological Positioning Attribute Process Regulator Genes Regulatory Element Reporter Resistance Risk Short Interspersed Nucleotide Elements Single Nucleotide Polymorphism Testing Tissues Untranslated RNA Validation Variant Virulence Factors base causal variant cell type diabetes risk differential expression disorder risk epigenetic variation epigenomics genome wide association study glucose uptake human genomics human subject improved in vivo insight insulin sensitivity insulin signaling knock-down loss of function mathematical model next generation novel novel therapeutics overexpression predictive modeling promoter risk variant tool trait transcription factor transcription factor USF transcriptomics translational medicine

项目摘要

ABSTRACT Insulin resistance (IR) is a sine qua non of Type 2 diabetes and a pathogenic factor in many other disease states. The molecular basis of IR is complex, and associated with many interweaving pathways. We have focused on nuclear mechanisms of IR, comprising the combined actions of transcription factors (TFs) and epigenomic modifiers. In the prior funding cycle we have identified several transcriptional regulators of cellular and tissue IR using advanced epigenomic strategies. For the upcoming cycle, we propose to shift to the study of human IR; specifically, the identification of transcriptional mechanisms that drive the development of IR in human adipocytes. Toward this end, we have generated chromatin state maps of primary adipocytes from insulin resistant and sensitive subjects, leading to the identification of thousands of enhancers with differential activity in IR. First, we will link these enhancers to their target genes using a novel mathematical model, and then validate a number of these predictions using CRISPRi. Next, we will assess which of these enhancers and genes show evidence of allelic imbalance, thus implying a genetic basis for their differential enrichment and predicting SNPs responsible for this effect. A massively parallel reporter assay will further implicate individual SNPs and TF motifs as candidates for drivers of IR, thus enabling the prediction of upstream regulators that bind and activate the enhancers. Finally, we will validate causal SNPs using base editing in cultured adipocytes testing their effects on target gene expression and insulin sensitivity. We will also validate candidate upstream regulators using a combination of gain- and loss-of-function approaches in vitro and in vivo. The key deliverable of this proposal will be the elucidation of the detailed transcriptional mechanisms underlying noncoding variation leading to human IR.

摘要