Targeting LRH-1 - Phospholipid Signaling in Metabolic Pathways

靶向 LRH-1 - 代谢途径中的磷脂信号传导

• 批准号: 9045615
• 负责人: Eric A Ortlund
• 金额: $ 33.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045615
• 关键词: Affect; Agonist; American; Antidiabetic Drugs; Automobile Driving; Bile Acids; Binding; Cell Nucleus; Complex; Coupled; Development; Diabetes Mellitus; Diabetic mouse; Disease; Disease Progression; Epidemic; Fatty acid glycerol esters; Goals; Head; Homeostasis; Homologous Gene; Human; In Vitro; Insulin; Intestines; Knock-out; Lecithin; Length; Ligand Binding; Ligands; Lipids; Liver; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methods; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Orphan Receptor; Nuclear Receptors; Pathway interactions; Phospholipid Signaling Pathway; Phospholipids; Population; Prediabetes syndrome; Property; Proteins; Receptor Activation; Research; Serum; Signal Transduction; Specificity; Structure; Surface; Tail; Testing; Therapeutic; blood glucose regulation; design; diabetic; glucose tolerance; high risk; improved; innovation; lipid metabolism; neoplastic; prevent; receptor; receptor binding; receptor function; small molecule; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Diabetes is a growing epidemic that currently affects over 25 million people in the US. The majority of these cases (90-95%) are type 2 diabetes, characterized by a diminished ability to respond to insulin. More alarming is that an estimated 54 million Americans have pre-diabetes, a condition that puts them at high risk for developing type 2 diabetes. New ways to manage this disease in an insulin independent manner are urgently needed. Recently, an unusual phospholipid, dilauroylphosphatidylcholine (PC 12:0-12:0; DLPC), has shown promising antidiabetic properties - lowering serum lipid levels, reducing fat accumulation in the liver, and improving glucose tolerance in diabetic mice when administered orally. Conditional knockout studies revealed that these effects were completely dependent on the orphan nuclear receptor liver receptor homologue-1 (LRH-1), thus identifying a new LRH-1 - DLPC signaling axis involved in bile acid metabolism and glucose homeostasis. We show that DLPC binds directly to LRH-1 and that DLPC binding completely blocks corepressor binding in vitro. To target this pathway for the treatment of diabetes it is critical t determine the fundamental mechanism governing the specific activation of LRH-1 by DLPC. We have determined the structure of the LRH-1 - DLPC complex to 1.9 ¿, which shows that DLPC binds very differently than the current best LRH-1 synthetic agonists. We will capitalize on this structure along with several recent innovations in our lab to identify the mechanisms driving this unique activity to enhance the potency of potential therapeutics targeting LRH-1 for the treatment of metabolic diseases. The Specific Aims of this proposal are as follows: 1. To determine LRH-1's phospholipid specificity in vitro, 2. To define the interaction surface between DLPC and LRH-1 and to connect these interactions with receptor function, 3. To determine the structure and dynamics of the apoLRH-1 - corepressor complex

描述（由申请人提供）：糖尿病是一种日益严重的流行病，目前影响美国超过 2500 万人。这些病例中的大多数 (90-95%) 是 2 型糖尿病，其特点是对胰岛素的反应能力下降。更令人担忧的是，估计有 5400 万美国人患有糖尿病前期，这种状况使他们面临患 2 型糖尿病的高风险。迫切需要以不依赖胰岛素​​的方式治疗这种疾病的新方法。最近，一种不寻常的磷脂，二月桂酰磷脂酰胆碱（PC 12:0-12:0；DLPC），在口服给药时显示出有希望的抗糖尿病特性——降低血清脂质水平，减少肝脏中的脂肪积累，并改善糖尿病小鼠的葡萄糖耐量。条件敲除研究表明，这些作用完全依赖于孤儿核受体肝受体同源物-1 (LRH-1)，从而确定了参与胆汁酸代谢和葡萄糖稳态的新LRH-1 - DLPC 信号轴。我们证明 DLPC 直接与 LRH-1 结合，并且 DLPC 结合在体外完全阻断辅阻遏物结合。为了靶向该途径来治疗糖尿病，确定控制 DLPC 特异性激活 LRH-1 的基本机制至关重要。我们已经确定了 LRH-1 - DLPC 复合物的结构为 1.9 ¿，这表明 DLPC 的结合与目前最好的 LRH-1 合成激动剂有很大不同。我们将利用这种结构以及我们实验室最近的几项创新来确定驱动这种独特活动的机制，以增强针对 LRH-1 的潜在疗法治疗代谢疾病的效力。该提案的具体目标如下： 1. 确定 LRH-1 的体外磷脂特异性， 2. 定义 DLPC 和 LRH-1 之间的相互作用表面，并将这些相互作用与受体功能联系起来， 3. 确定 apoLRH-1 - 辅阻遏物复合物的结构和动力学

项目成果

A Structural Investigation into Oct4 Regulation by Orphan Nuclear Receptors, Germ Cell Nuclear Factor (GCNF), and Liver Receptor Homolog-1 (LRH-1).

• DOI: 10.1016/j.jmb.2016.10.025
• 发表时间: 2016-12-04
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Weikum ER;Tuntland ML;Murphy MN;Ortlund EA
• 通讯作者: Ortlund EA

Phospholipid--driven gene regulation.

• DOI: 10.1016/j.febslet.2013.01.004
• 发表时间: 2013-04-17
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: Musille PM;Kohn JA;Ortlund EA
• 通讯作者: Ortlund EA

Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes.

• DOI: 10.1093/nar/gkx509
• 发表时间: 2017-08-21
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Weikum ER;de Vera IMS;Nwachukwu JC;Hudson WH;Nettles KW;Kojetin DJ;Ortlund EA
• 通讯作者: Ortlund EA