The role of TCF7L2 in hepatic glucose metabolism in vivo

TCF7L2在体内肝糖代谢中的作用

• 批准号: 8700710
• 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
• 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/8700710
• 关键词: Address; Adenoviruses; Adult; Affect; Alleles; Area; Binding; Bioinformatics; Blood Glucose; Blood Vessels; Candidate Disease Gene; Cells; Computational Technique; 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; Genomics; Glucose Clamp; Goals; 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; 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; human TCF7L2 protein; in vivo; insulin sensitivity; interest; novel; programs; public health relevance; research study; skills; transcription factor

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（申请人提供）：转录因子7样2（TCF 7 L2）基因内的单核苷酸多态性（SNP）一直与全球多个人群中2型糖尿病（T2 DM）风险升高相关，但TCF 7 L2影响T2 DM发生的重要途径的机制仍知之甚少。解决这个问题是非常重要的，主要是因为对T2 DM候选基因的功能研究将揭示影响T2 DM中高度干扰的重要生理过程的新分子途径。在几项人类研究中，“高危”SNP（rs7903146）的T等位基因携带者具有受损的肝葡萄糖生成（HGP）和肝胰岛素敏感性。Norton博士实验室的初步发现表明，TCF 7 L2的沉默在体外显著上调HGP，强烈支持TCF 7 L2在HGP途径中的作用。本研究的目的是建立T2 DM候选基因TCF 7 L2在体内HGP中的功能作用，并研究TCF 7 L2影响肝脏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组合将被用来解决中心假设，即TCF 7 L2是体内HGP的主要调节因子，TCF 7 L2在肝脏中对关键代谢基因的转录控制是这种调节的潜在机制。这项建议的主要培训内容是新技能的获得、改进和应用，重点是两个领域：㈠综合生理学; ㈡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开展尖端糖尿病研究极其宝贵，并且这些领域与本项目的科学目标高度融合。此外，该提案的科学目标将与密集的职业发展计划相结合，该计划将包括graneclampsia和translational science的正式课程。UTHSCSA的糖尿病部门由该项目的导师DeFronzo博士担任主席，是进行这项研究并进一步提高Norton博士在糖尿病研究方面的专业知识的理想环境。