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：
9143741
负责人：
Michael Lee Stitzel
金额：
$ 24.9万
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/9143741
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 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 Morbidity - disease rate Mus Neurologic Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences Pancreas Participant Pattern Peripheral Nervous System Diseases Phase Phenotype Preventive Intervention 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 chromosome conformation capture 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：人类胰岛及其其非编码变化的调查发展前体。该研究项目的目的是了解遗传变异在非 - 蛋白质编码，人类胰岛功能中基因组的调节区域和功能障碍。胰岛中分泌胰岛素分泌细胞负责维持正常血糖水平。 2型糖尿病（T2D）导致这些糖尿病的进行性失败细胞在血糖水平升高的情况下分泌胰岛素，是美国和全球的大量发病率和死亡率。发展 T2D涉及个人基因与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个区域赋予开发T2D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。该项目使用基因组 - 广泛的染色质分析，以识别有助于通过确定哪个候选监管区域作为增强子，T2D，人胰岛中的消音器或绝缘子（特定目的1），哪些元素包含改变基因表达在成人人类胰岛中的变体（特定目标2）或胰腺前体细胞（特定目标3）。这些目标的完成将提供详细的增强器，消音器和绝缘子元素的功能注释，识别密钥调节元件促进剂的相互作用，并确定与T2D相关和其他如何相关的变体改变了它们在人类胰腺前体或成熟胰岛细胞中的功能。