The role of TCF7L2 in hepatic glucose metabolism in vivo

描述(申请人提供)：转录因子7-样2(TCF7L2)基因内的单核苷酸多态(SNP)在世界各地的多个人群中一直与2型糖尿病(T2 DM)的高风险相关，但TCF7L2影响对T2 DM发展至关重要的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T2 DM候选基因的功能研究将揭示影响T2 DM高度干扰的重要生理过程的新的分子途径。在几项人类研究中，高危SNP的T等位基因携带者(Rs7903146)损害了肝脏葡萄糖产生(HGP)和肝脏胰岛素敏感性。Norton博士实验室的初步研究结果表明，在体外，沉默TCF7L2显著上调HGP，有力地支持TCF7L2在HGP途径中的作用。本研究的目的是确定T2 DM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将被用来解决核心假设，即TCF7L2是体内HGP的主要调节因子，并且TCF7L2在肝脏中对关键代谢基因的转录控制是这一调节的潜在机制。这项建议的主要培训内容是新技能的获取、改进和应用，重点放在两个领域：(1)综合生理学；(2)功能基因组学和生物信息学。之所以选择这些专题领域，是因为目前关于这些领域的知识对开展尖端糖尿病研究非常有价值，而且这些领域与本项目的科学目标是紧密联系和高度结合的。此外，这项提议的科学目标将与密集的职业发展计划相结合，该计划将包括赠款和翻译科学方面的正式课程。UTHSCSA的糖尿病部门由该项目的导师DeFronzo博士担任主席，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。

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.