The role of TCF7L2 in hepatic glucose metabolism in vivo

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）在世界各地的多个人群中一直与2型糖尿病（T2DM）风险升高相关，但TCF7L2影响T2DM发展重要途径的机制仍然知之甚少。解决这个问题非常重要，主要是因为对T2DM候选基因的功能研究将揭示影响T2DM中高度紊乱的重要生理过程的新分子途径。在几项人体研究中，携带“高危”SNP (rs7903146) t等位基因的人会损害肝脏葡萄糖生成（HGP）和肝脏胰岛素敏感性。诺顿博士实验室的初步研究结果表明，TCF7L2的沉默在体外显著上调HGP，有力地支持了TCF7L2在HGP通路中的作用。本课题旨在确定T2DM候选基因TCF7L2在体内HGP中的功能作用，并探讨TCF7L2影响肝脏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，即TCF7L2是体内HGP的主要调节剂，TCF7L2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。该建议的主要培训内容是新技能的获取、改进和应用，重点关注两个领域：(i)综合生理学，（ii）功能基因组学和生物信息学。之所以选择这些主题领域，是因为目前这些领域的知识对于开展前沿的糖尿病研究是非常有价值的，而且这些领域与本项目的科学目标是有凝聚力和高度融合的。此外，本提案的科学目标将与密集的职业发展计划相结合，其中将包括资助和转化科学方面的正式课程。UTHSCSA的糖尿病部门由该项目的导师DeFronzo博士主持，是开展这项研究的理想环境，并进一步提高诺顿博士在糖尿病研究方面的专业知识。

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.