Endogenous HNF4 Ligands in Physiology and Disease

生理学和疾病中的内源性 HNF4 配体

• 批准号: 6959131
• 负责人: FRANCES M. SLADEK
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6959131
• 关键词: RNA interference; SDS polyacrylamide gel electrophoresis; atherosclerosis; disease /disorder etiology; gas chromatography mass spectrometry; gene expression; gene mutation; genetic transcription; hemophilia As; hepatitis; histogenesis; laboratory mouse; laboratory rat; linolenate; liver disorder; liver function; noninsulin dependent diabetes mellitus; nuclear receptors; pathologic process; physiology; receptor binding; receptor expression; regulatory gene; tissue /cell culture; transcription factor; transfection

DESCRIPTION (provided by applicant): Hepatocyte nuclear factor 4 (HNF4) is an essential liver-enriched transcription factor that plays a central role in liver development and differentiation. HNF4 is mutated in an inherited form of type Il diabetes, Maturity Onset Diabetes of the Young 1 (MODY1), and regulates the expression of many genes responsible for liver function, including those in intermediary metabolism - i.e., glucose, lipid, amino acid, xenobiotic and drug metabolism - and blood maintenance as well as other transcription factors. Through its role in the liver and other tissues where it is also expressed - pancreas, kidney, intestine and colon - HNF4 is linked to several human diseases in addition to diabetes, including atherosclerosis, hemophilia, hepatitis and possibly cancer. HNF4 is also one of the most highly conserved members of the nuclear receptor superfamily and yet a ligand for h has not yet been identified. In this proposal, we use a novel method to identify an endogenous dietary compound that binds in the ligand binding pocket of HNF4 expressed in mammalian cells and mouse liver. In the two specific aims of this R21 we propose to: 1) determine whether the binding of the compound affects HNF4 function; 2) determine the physiological and pathological conditions under which HNF4 binds the compound. Results from these studies will not only enhance significantly our understanding of how HNF4 regulates transcription in the liver, kidney and the GI track but could also impact the use of HNF4 as a drug target for diabetes and possibly other diseases.

描述（由申请人提供）：肝细胞核因子4（HNF 4）是一种必需的肝脏富集转录因子，在肝脏发育和分化中起核心作用。HNF 4在II型糖尿病的遗传形式中突变，即年轻人成熟型糖尿病1（MODY 1），并调节许多负责肝功能的基因的表达，包括中间代谢中的基因-即，葡萄糖、脂质、氨基酸、异生物质和药物代谢-和血液维持以及其它转录因子。通过它在肝脏和其他组织中的作用，它也表达-胰腺，肾脏，肠和结肠-HNF 4与糖尿病以外的几种人类疾病有关，包括动脉粥样硬化，血友病，肝炎和可能的癌症。HNF 4也是核受体超家族中最保守的成员之一，但尚未鉴定出HNF 4的配体。在这个建议中，我们使用一种新的方法来确定内源性的饮食化合物，结合在哺乳动物细胞和小鼠肝脏中表达的HNF 4的配体结合口袋。在R21的两个具体目标中，我们建议： 1)确定所述化合物的结合是否影响HNF 4功能; 2)确定HNF 4结合化合物的生理和病理条件。 这些研究的结果不仅将大大提高我们对HNF 4如何调节肝脏，肾脏和GI轨道转录的理解，而且还可能影响HNF 4作为糖尿病和其他疾病的药物靶点的使用。