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Investigation of noncoding variation in human pancreatic islets and their develop

人胰岛非编码变异的研究及其发展

基本信息

批准号：
9037997
负责人：
Michael Lee Stitzel
金额：
$ 4.73万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-20 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9037997
关键词：
Address Adult Affect Alleles Beta Cell Binding Biological Assay Biological Models Blindness Blood Glucose Blood Vessels Cardiovascular Diseases Cell Differentiation process Cell Line Cells ChIP-seq Chromatin Chromosomes Code Collaborations Complex DNase I hypersensitive sites sequencing Data Deoxyribonucleases Development Diabetes Mellitus Disease Distal EP300 gene Economic Burden Elements Enhancers Environment Epigenetic Process Failure Foundations Functional disorder Funding Gene Expression Generations Genes Genetic Genetic Enhancer Element Genetic Risk Genetic Variation Genome Genotype Goals Health Histone H3 Human Hypersensitivity In Vitro Individual Insulator Elements Insulin Insulin Resistance Investigation Islet Cell Islets of Langerhans Kidney Failure LacZ Genes Lead Letters Luciferases Measures Mediator of activation protein Methylation Molecular Molecular Conformation Morbidity - disease rate Mus Neurologic Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences Pancreas Participant Pattern Peripheral Nervous System Diseases Phase Phenotype Proteins Protocols documentation Public Health RNA Reagent Regulatory Element Reporter Research Personnel Research Project Grants Risk Risk Factors Role Sampling Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Therapeutic Intervention Tissues Training Activity Transcriptional Silencer Elements United States Untranslated RNA Variant base cell type cohesin cost diabetes risk genetic association genome wide association study genome-wide health economics histone modification induced pluripotent stem cell islet mortality pancreatic islet function precursor cell promoter spatiotemporal stem

项目摘要

Title: Investigation of noncoding variation in human pancreatic islets and their developmental precursors. The goal of this research project is to understand the role of genetic variation in non- protein coding, regulatory regions of the genome in human pancreatic islet function and dysfunction. Insulin-secreting cells in the islet are responsible for maintaining normal blood glucose levels. Type 2 diabetes (T2D) results from progressive failure of these cells to secrete insulin in the face of increasing blood glucose levels and is the cause of substantial morbidity and mortality in the United States and worldwide. Development of T2D involves complex interactions between an individual's genes and environment. Genetic association studies have identified approximately 40 regions in the genome that confer risk of developing T2D. The majority of these regions does not contain coding sequence variants, but instead contains non-coding variants. This project uses genome- wide chromatin profiling to identify the critical regulatory elements that contribute to T2D by determining which of the candidate regulatory regions function as enhancers, silencers, or insulators in human islets (Specific Aim 1) and which elements contain variants that alter gene expression in adult human islets (Specific Aim 2) or in pancreatic precursor cells (Specific Aim 3). Completion of these aims will provide detailed functional annotation of enhancer, silencer, and insulator elements, identify key regulatory element-promoter interactions, and identify how T2D-associated and other variants alter their function in human pancreatic precursor or mature islet cells.

标题：人胰岛非编码变异及其与胰岛素抵抗的关系发展的先驱。本研究项目的目标是了解遗传变异在非遗传性疾病中的作用。人胰岛功能基因组的蛋白质编码、调控区，功能障碍胰岛中的胰岛素分泌细胞负责维持正常的血糖水平。2型糖尿病（T2 D）是由这些疾病的进行性失败引起的。细胞分泌胰岛素在面对增加的血糖水平，是原因美国和世界各地的发病率和死亡率很高。发展 T2 D的发病涉及个体基因和环境之间的复杂相互作用。遗传关联研究已经确定了基因组中大约40个区域，有发展为T2 D的风险。这些区域中的大多数不包含编码序列变体，而是包含非编码变体。这个项目使用基因组- 广泛的染色质分析，以确定关键的调控元件，有助于通过确定哪些候选调控区作为增强子起作用，人类胰岛中的消音器或绝缘体（具体目标1）以及改变成人胰岛（特异性目标2）或胰腺中基因表达的变体前体细胞（具体目标3）。这些目标的实现将提供详细的增强子、消音器和绝缘子元件的功能注释，识别键调节元件-启动子相互作用，并确定如何T2 D相关和其他变体改变它们在人胰腺前体或成熟胰岛细胞中的功能。