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: 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
• 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

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) 一直与世界各地多个人群中 2 型糖尿病 (T2DM) 风险升高相关，但TCF7L2 影响 T2DM 发展的重要途径的机制仍知之甚少。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 中高度干扰的重要生理过程的新分子途径。在多项人类研究中，“高危”SNP (rs7903146) 的 T 等位基因携带者的肝脏葡萄糖生成 (HGP) 和肝脏胰岛素敏感性受损。 Norton 博士实验室的初步研究结果表明，TCF7L2 的沉默在体外显着上调 HGP，有力地支持了 TCF7L2 在 HGP 途径中的作用。本提案的目的是建立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，即 TCF7L2 是体内 HGP 的主要调节因子，并且肝脏中 TCF7L2 对关键代谢基因的转录控制是这种调节的潜在机制。该提案的主要培训内容是新技能的获取、完善和应用，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。选择这些主题领域是因为目前这些领域的知识对于开展尖端糖尿病研究非常有价值，并且这些领域与该项目的科学目标具有凝聚力和高度整合性。此外，该提案的科学目标将与密集的职业发展计划相结合，其中包括资助学和转化科学的正式课程。 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。

项目成果

The mechanisms of genome-wide target gene regulation by TCF7L2 in liver cells.

肝细胞中 TCF7L2 的全基因组靶基因调控机制。

• 发表时间: 2014-12-16
• 影响因子: 14.9
• 作者: Norton, Luke;Chen, Xi;Fourcaudot, Marcel;Acharya, Nikhil K;DeFronzo, Ralph A;Heikkinen, Sami
• 通讯作者: Heikkinen, Sami

Sodium-glucose co-transporter (SGLT) and glucose transporter (GLUT) expression in the kidney of type 2 diabetic subjects.

2 型糖尿病受试者肾脏中钠-葡萄糖协同转运蛋白 (SGLT) 和葡萄糖转运蛋白 (GLUT) 的表达。

• 发表时间: 2017-09
• 作者: Norton, Luke;Shannon, Christopher E;Fourcaudot, Marcel;Hu, Cheng;Wang, Niansong;Ren, Wei;Song, Jun;Abdul;DeFronzo, Ralph A;Ren, Jimmy;Jia, Weiping
• 通讯作者: Jia, Weiping

Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes.

吡格列酮抑制肝细胞中线粒体丙酮酸代谢和葡萄糖产生。

• 发表时间: 2017-02
• 作者: Shannon, Christopher E;Daniele, Giuseppe;Galindo, Cynthia;Abdul;DeFronzo, Ralph A;Norton, Luke
• 通讯作者: Norton, Luke