Role of Estrogen Related Receptors in Age Related Kidney Disease

拟议中的研究将测试线粒体功能障碍和炎症增加的假设， 介导与年龄相关的肾病。我们认为雌激素相关受体ERRα的表达增加 和ERRγ改善线粒体功能，并减少cGAS-STING信号传导，细胞衰老和 炎症，逆转与年龄相关的肾脏疾病。此外，ERRs对衰老的影响， 炎症和纤维化是cGAS-STING依赖性的。此外，ERRα和ERRγ的表达增加， 或抑制cGAS-STING信号传导防止由叶酸、LPS或 缺血/再灌注 在特定目的1中，我们将检验肾小管ERRα或ERRγ增加将改善 线粒体功能和炎症以及逆转与年龄相关的肾脏疾病。我们将确定：A） 肾小管ERRα或ERRγ或同时ERRα/ERRγ表达增加对肾脏的影响 B）如果肾小管增加，则ERRs阻止急性 由a）叶酸，B）LPS，或c）缺血/再灌注介导的肾损伤。这些研究的基本原理是， 所有三种模型均导致肾脏中ERRα和ERRγ表达降低; C）增加的直接作用 人类近端肾小管细胞中ERRα、ERRγ或同时ERRα和ERRγ的表达。 在《特异性目的2》中，我们将检验ERRα或ERRγ逆转炎症的作用的假设。 和肾脏疾病是通过cGAS-STING依赖性机制介导的。我们将确定 A）cGAS：用ERR处理的全身性或肾特异性cGAS敲除小鼠; B）STING： C）我们将确定用ERR治疗的小鼠是否为全身性或肾特异性STING敲除小鼠; 与STING抑制剂联合使用可预防由a）叶酸、B）LPS或c）缺血/再灌注介导的急性肾损伤。 这些研究的基本原理是，所有三种模型都导致肾脏中cGAS-STING表达增加。 创新：1）这些研究将确定是否诱导性增加ERR-α和ERR-γ的表达， 肾小管将改善线粒体功能障碍，cGAS-STING介导的炎症和年龄相关的 肾病2)虽然已经研究了ERRs在调节线粒体功能中的作用，主要是在 在其他靶器官中，ERRs在炎症调节中的作用是新的，并且尚未在本领域中研究。 肾为此，我们将进行机制研究，以确定cGAS-STING在调节细胞凋亡中的作用。 炎症和ERR在肾脏中的作用。

The proposed studies will test the hypothesis that mitochondrial dysfunction and increased inflammation mediates age-related kidney disease. We propose that increased expression of estrogen related receptors ERRα and ERRγ improves mitochondrial function, and decreases cGAS-STING signaling, cellular senescence and inflammation, which reverses age-related kidney disease. In addition, the effects of ERRs on senescence, inflammation, and fibrosis are cGAS-STING dependent. Furthermore, increased expression of ERRα and ERRγ or inhibition of cGAS-STING signaling prevents acute kidney injury mediated by folic acid, LPS, or ischemia/reperfusion In SPECIFIC AIM 1 we will test the hypothesis that increased renal tubular ERRα or ERRγ will improve mitochondrial function and inflammation and reverse age-related kidney disease. We will determine: A) the effects of renal tubular ERRα or ERRγ or simultaneous ERRα/ERRγ increased expression on kidney mitochondrial function, inflammation and kidney disease; B) if renal tubular increases in ERRs prevents acute kidney injury mediated by a) folic acid, b) LPS, or c) ischemia/reperfusion. The rationale for these studies is that all three models result in decreased ERRα and ERRγ expression in the kidneys; C) direct effects of increased expression of ERRα, ERRγ, or simultaneous ERRα and ERRγ in human proximal tubular cells. In SPECIFIC AIM 2 we will test the hypothesis that the effects of ERRα or ERRγ to reverse inflammation and kidney disease in aging are mediated via a cGAS-STING dependent mechanism. We will determine the roles of A) cGAS: generalized or kidney specific cGAS knockout mice treated with ERR; B) STING: generalized or kidney specific STING knockout mice treated with ERR; C) We will determine if treatment of mice with STING inhibitor prevents acute kidney injury mediated by a) folic acid, b) LPS, or c) ischemia/reperfusion. The rationale for these studies is that all three models result in increased cGAS-STING expression in the kidneys. INNOVATION: 1) These studies will determine if inducible increased expression of ERR-α and ERR-γ in the renal tubules will improve mitochondrial dysfunction, cGAS-STING mediated inflammation and age-related kidney disease. 2) While the effects of ERRs in regulation of mitochondrial function has been studied, mainly in other target organs, the effects of ERRs in regulation of inflammation is novel and has not been studied in the kidney. To this end we will perform mechanistic studies to determine the role of cGAS-STING in regulating inflammation and the effects of ERR in the kidney.