Role of Estrogen Related Receptors in Age Related Kidney Disease

拟议的研究将检验线粒体功能障碍和炎症增加的假设 调节与年龄相关的肾脏疾病。我们认为雌激素相关受体ERRα的表达增加 ERRγ可改善线粒体功能，减少cGAS-STING信号转导，细胞衰老和 炎症，逆转与年龄相关的肾脏疾病。此外，错误对衰老的影响， 炎症和纤维化是cGAS依赖的。此外，ERRα和ERRγ的表达增加 或抑制cGAS-STING信号可预防由叶酸、内毒素或 缺血/再灌流 在特定的目标1中，我们将检验这样的假设，即增加的肾小管ERRα或ERRγ将会改善 线粒体功能和炎症，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对肾脏表达的影响 线粒体功能、炎症和肾脏疾病；B)如果肾小管错误增加，则可防止急性 肾损伤由a)叶酸、b)内毒素或c)缺血/再灌流所致。这些研究的基本原理是 所有三种模型都导致肾脏ERRα和ERRγ表达减少；C)增加 人近端肾小管上皮细胞ERRα、ERRγ或同时表达ERRα和ERRγ 在特定的目标2中，我们将检验ERRα或ERRγ逆转炎症的作用这一假设 而衰老中的肾脏疾病是通过cGAS依赖机制介导的。我们将决定 A)cGAS的作用：用ERR治疗全身性或肾脏特异性cGAS基因敲除小鼠；B)刺痛： 用ERR治疗全身性或肾脏特异性叮咬基因敲除小鼠；C)我们将确定是否治疗小鼠 使用STING抑制剂可预防由a)叶酸、b)内毒素或c)缺血/再灌流引起的急性肾损伤。 这些研究的基本原理是，所有这三种模型都会导致肾脏中cGAS刺蛋白表达增加。 创新：1)这些研究将确定ERR-α和ERR-γ的表达是否可诱导增加 肾小管可改善线粒体功能障碍、cGAS-STING介导的炎症和年龄相关 肾脏疾病。2)虽然已经研究了错误在线粒体功能调节中的作用，主要是在 对于其他靶器官，ERRS在调节炎症中的作用是新的，还没有在 肾脏。为此，我们将进行机制研究，以确定cGAS-STING在调节中的作用 肾脏的炎症和ERR的影响。

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.