The role of TCF7L2 in hepatic glucose metabolism in vivo

TCF7L2在体内肝糖代谢中的作用

基本信息

批准号：
9039586
负责人：
Luke Norton
金额：
$ 10.97万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2014-04-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039586
关键词：
Address Adenoviruses Adult Affect Alleles Area Binding Bioinformatics Blood Glucose Blood Vessels Candidate Disease Gene Cells Computer Analysis Coupled Data Defect Development Development Plans Diabetes Mellitus Disease Environment Epidemic Euglycemic Clamping Failure Fasting Figs - dietary Foundations Future Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genomic approach Genomics Glucose Clamp Goals HNF4A gene Hepatic Hepatocyte Human Hyperglycemia In Vitro Individual Insulin Resistance Investigation Knowledge Laboratory Finding Lead Liver Mentors Metabolic Metabolic Pathway Mind Molecular Molecular Biology Molecular Genetics Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus OGTT Pancreas Pathogenesis Pathway interactions Patients Physiological Physiological Processes Physiology Play Population Publishing Radioisotopes Rattus Regulation Regulator Genes Research Risk Risk Factors Role Single Nucleotide Polymorphism Solid Susceptibility Gene TCF7L2 gene Techniques Technology Testing Time Tissues Tracer Training Training Activity Transcriptional Regulation Translational Research blood glucose regulation career career development clinically significant design diabetic patient functional genomics genome wide association study glucose metabolism glucose production glucose tolerance in vivo insulin sensitivity interest novel novel therapeutics programs public health relevance research study skills transcription factor

项目摘要

DESCRIPTION (provided by applicant): Single-nucleotide polymorphisms (SNP) within the transcription factor 7-like 2 (TCF7L2) gene have been consistently associated with an elevated risk for type 2 diabetes (T2DM) in multiple populations throughout the world, but the mechanisms by which TCF7L2 affects the pathways important for the development of T2DM are still poorly understood. Addressing this question is of major importance, primarily because functional investigations into T2DM candidate genes will reveal novel molecular pathways that affect important physiological processes that are highly disturbed in T2DM. In several human studies, carriers of the T-allele for the "at-risk" SNP (rs7903146) have impaired hepatic glucose production (HGP) and hepatic insulin sensitivity. Preliminary findings from the laboratory of Dr Norton demonstrating that silencing of TCF7L2 markedly up- regulates HGP in vitro, strongly support a role for TCF7L2 in the pathways of HGP. The aim of this proposal is to establish the functional role of the T2DM candidate gene TCF7L2 in HGP in vivo, and to investigate the molecular mechanisms by which TCF7L2 affects the pathways of glucose metabolism in the liver. A combination of integrative physiology and genomics approaches will be used to address the central hypothesis that TCF7L2 is a major regulator of HGP in vivo and that transcriptional control of key metabolic genes by TCF7L2 in the liver is the underlying mechanism of this regulation. The major training component of this proposal is the acquisition, refinement and application of new skills, with focus on two areas: (i) integrated physiology, and (ii) functional genomics and bioinformatics. These thematic areas were selected because at the present time knowledge about these areas is extremely valuable to conduct cutting-edge diabetes research, and these areas are cohesive and highly integrated with the scientific goals of this project. In addition, the scientific objectives of this proposal will be coupled with an intensive career development plan that will include formal coursework in grantsmanship and translational science. The Diabetes Division at the UTHSCSA, chaired by the mentor on this project Dr DeFronzo, is the ideal environment in which to perform this research and to further enhance Dr Norton's expertise in diabetes research.

描述（由申请人提供）：转录因子7样2（TCF7L2）基因内的单核苷酸多态性（SNP）一直与全世界多种种群中2型糖尿病（T2DM）的风险升高相关，但tcf7l2对TCF7L2的机制仍然对TCF7L2的发展仍然很糟糕。解决这个问题至关重要，主要是因为对T2DM候选基因的功能研究将揭示出影响重要生理过程的新型分子途径，这些过程在T2DM中受到高度干扰。在几项人类研究中，“处于危险” SNP（rs7903146）的T型载体损害了肝葡萄糖产生（HGP）和肝胰岛素敏感性。 Norton博士实验室的初步发现表明，TCF7L2的沉默明显地调节了HGP的体外，强烈支持TCF7L2在HGP途径中的作用。该建议的目的是建立T2DM候选基因TCF7L2在体内HGP中的功能作用，并研究TCF7L2影响肝脏中葡萄糖代谢途径的分子机制。综合生理学和基因组学方法的结合将用于解决中心假设：TCF7L2是体内HGP的主要调节剂，并且TCF7L2在肝脏中对关键代谢基因的转录控制是该法规的潜在机制。该提案的主要培训组成部分是新技能的获取，改进和应用，重点是两个领域：（i）综合生理学，以及（ii）功能基因组学和生物信息学。之所以选择这些主题领域，是因为目前有关这些领域的知识对于进行最先进的糖尿病研究非常有价值，并且这些领域具有凝聚力，并且与该项目的科学目标高度融合。此外，该提案的科学目标将与一项密集的职业发展计划相结合，其中将包括授予技巧和转化科学的正式课程。由该项目Defronzo博士主持的UTHSCSA的糖尿病部门是进行这项研究并进一步增强Norton博士在糖尿病研究方面的专业知识的理想环境。