Function of the Nuclear Receptor LRH-1

核受体LRH-1的功能

• 批准号: 7632978
• 负责人: DAVID D MOORE
• 金额: $ 38.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632978
• 关键词: Agonist; Antidiabetic Drugs; Bile Acids; Binding; Cell Line; Cells; Cholesterol Homeostasis; DNA Binding; Development; Diabetic mouse; Disease Pathway; Disease model; Embryonic Development; Enzymes; Exocrine pancreas; Fatty Acids; Gene Expression; Genes; Goals; Hepatic; Hepatocyte; Homeostasis; Hormones; In Vitro; Individual; Inflammatory Bowel Diseases; Intestines; Knock-out; Knockout Mice; Lecithin; Ligands; Liver; Metabolic; Metabolic Diseases; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Nuclear Orphan Receptor; Nuclear Receptors; Orphan; Ovary; Phospholipids; Receptor Signaling; Relative (related person); Reporting; Role; Series; Side; Staging; Structure; Testing; Therapeutic; Transactivation; Work; base; blood glucose regulation; db/db mouse; diabetic; embryonic stem cell; improved; insight; insulin sensitivity; liver function; monomer; novel; public health relevance; receptor; tool

DESCRIPTION (provided by applicant): Recent x-ray crystal studies have identified phospholipids as potential ligands, but their relevance to LRH-1 transactivation has been unclear. We have found that unusual phosphatidylcholine (PC) species with two C11:0 (diundecanoyl; DUPC) or two C12:0 (dilauroyl; DLPC) fatty acid side chains are potent activators of LRH-1 transactivation. Both compounds are agonists that increase coactivator binding both in vitro and in cells. In preliminary studies, treatment of mice with either DUPC or DLPC induces expression of bile acid biosynthetic enzymes and increases overall bile acid pool size. DLPC treatment also markedly improves glucose homeostasis in diabetic db/db mice. The goal of this proposal is to test the hypothesis that LRH-1 is a key metabolic regulator with agonist ligands that have beneficial effects in metabolic disorders. The aims are to: 1. Define the impact of novel LRH-1 agonist ligands on gene expression and function in cultured hepatocytes and intestinal cell lines. 2. Define the impact of novel LRH-1 agonist ligands on gene expression and function in normal mouse liver and intestine. 3. Define the impact of novel LRH-1 ligands on gene expression and function in murine disease models, particularly type 2 diabetes and inflammatory bowel disease. We believe that these studies will produce new insights into metabolic homeostasis, and that they have the potential to open up a completely new avenue to approaching metabolic disorders. PUBLIC HEALTH RELEVANCE: This project is based on the discovery of a new class of potential hormones. These compounds activate two poorly understood nuclear hormone receptors and alter liver functions. They also show antidiabetic effects, and a particular goal is to explore how they work and whether they have potential therapeutic utility.

描述（由申请人提供）：最近的X射线晶体研究已确定磷脂为潜在的配体，但其与LRH-1反式激活的相关性尚不清楚。我们已经发现具有两个C11：0（二十一烷酰基; DUPC）或两个C12：0（二月桂酰基; DLPC）脂肪酸侧链的不寻常的磷脂酰胆碱（PC）种类是LRH-1反式激活的有效激活剂。这两种化合物都是激动剂，在体外和细胞中增加辅活化剂结合。在初步研究中，用DUPC或DLPC处理小鼠诱导胆汁酸生物合成酶的表达并增加总胆汁酸池大小。DLPC治疗还显著改善糖尿病db/db小鼠中的葡萄糖稳态。该提案的目的是检验LRH-1是一种关键的代谢调节剂，其激动剂配体在代谢紊乱中具有有益作用的假设。目的是：1.确定新型LRH-1激动剂配体对培养的肝细胞和肠细胞系中基因表达和功能的影响。2.确定新型LRH-1激动剂配体对正常小鼠肝脏和肠道中基因表达和功能的影响。3.确定新型LRH-1配体对小鼠疾病模型（特别是2型糖尿病和炎症性肠病）中基因表达和功能的影响。我们相信，这些研究将产生新的见解代谢稳态，他们有可能开辟一个全新的途径来处理代谢紊乱。公共卫生相关性：该项目基于发现一类新的潜在激素。这些化合物激活两种知之甚少的核激素受体并改变肝功能。它们还表现出抗糖尿病作用，一个特别的目标是探索它们如何发挥作用以及它们是否具有潜在的治疗用途。