Targeting LRH-1 - Phospholipid Signaling in Metabolic Pathways

描述（由申请人提供）：糖尿病是一种日益增长的流行病，目前在美国影响超过2500万人。这些病例中的大多数（90-95%）是2型糖尿病，其特征是对胰岛素的反应能力下降。更令人担忧的是，估计有5400万美国人患有前驱糖尿病，这种情况使他们患2型糖尿病的风险很高。目前迫切需要以不依赖胰岛素的方式管理这种疾病的新方法。最近，一种不寻常的磷脂，二脲酰磷脂酰胆碱（PC 12:0-12:0； DLPC），显示出有希望的抗糖尿病特性-降低血脂水平，减少肝脏脂肪堆积，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)，从而确定了一个新的LRH-1 - DLPC信号轴参与胆酸代谢和葡萄糖稳态。我们发现DLPC直接与LRH-1结合，并且在体外完全阻断了辅抑制因子的结合。为了靶向这一途径治疗糖尿病，确定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与目前最好的LRH-1合成激动剂的结合非常不同。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治疗代谢性疾病的潜在疗法的效力。本建议的具体目的如下：2.体外测定LRH-1的磷脂特异性。2 .明确DLPC与LRH-1的相互作用面，并将这些相互作用与受体功能联系起来。确定apoLRH-1 -辅抑制因子复合物的结构和动力学

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