Role of Estrogen Related Receptors in Age Related Kidney Disease

雌激素相关受体在年龄相关性肾脏疾病中的作用

• 批准号: 10320972
• 负责人: MOSHE LEVI
• 金额: $ 47.95万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-21 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320972
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Age-Months; Aging; Agonist; Albumins; Bile Acids; Caloric Restriction; Cell Aging; Cells; Chronic Kidney Failure; Elderly; Excretory function; Female; Fibrosis; Folic Acid; G-Protein-Coupled Receptors; GPBAR1 gene; GTP-Binding Protein alpha Subunits, Gs; Generations; Human; Hypertension; Image; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Label; Life; Mediating; Metabolic syndrome; Microscope; Microscopy; Mitochondria; Modeling; Monitor; Mus; Nuclear Hormone Receptors; Organ; Persons; Population; Prevention strategy; Recovery; Regulation; Renal function; Renal tubule structure; Reperfusion Therapy; Resolution; Role; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; TNF gene; Testing; Three-Dimensional Imaging; Transforming Growth Factor beta; Tubular formation; adeno-associated viral vector; age group; age related; comorbidity; cytokine; estrogen-related receptor; farnesoid X-activated receptor; human old age (65+); improved; inhibitor; kidney fibrosis; male; microscopic imaging; mitochondrial dysfunction; novel; prevent; response; second harmonic; senescence; treatment strategy; urinary

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.

拟议的研究将检验线粒体功能障碍和炎症增加的假设 我们认为雌激素相关受体 ERRα 的表达增加会介导与年龄相关的肾脏疾病。 ERRγ 可改善线粒体功能，并减少 cGAS-STING 信号传导、细胞衰老和 炎症，可逆转与年龄相关的肾脏疾病。此外，ERR 对衰老的影响， 炎症和纤维化依赖于 cGAS-STING 此外，ERRα 和 ERRγ 表达增加。 或抑制 cGAS-STING 信号传导可预防由叶酸、LPS 或 缺血/再灌注 在具体目标 1 中，我们将检验肾小管 ERRα 或 ERRγ 增加会改善的假设 我们将确定：A) 线粒体功能和炎症以及逆转与年龄相关的肾脏疾病。 肾小管ERRα或ERRγ或同时ERRα/ERRγ表达增加对肾脏的影响 线粒体功能、炎症和肾脏疾病；B) 如果肾小管 ERR 增加可以预防急性肾病 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 表达减少 C) 增加的直接影响； 在人近端肾小管细胞中表达 ERRα、ERRγ 或同时表达 ERRα 和 ERRγ。 在 SPECIFIC AIM 2 中，我们将检验以下假设：ERRα 或 ERRγ 逆转炎症的作用 衰老过程中的肾脏疾病和肾脏疾病是通过 cGAS-STING 依赖性机制介导的。 A) cGAS 的作用：用 ERR 治疗的全身性或肾脏特异性 cGAS 敲除小鼠 B) STING： 用 ERR 治疗的全身或肾脏特异性 STING 敲除小鼠 C) 我们将确定是否对小鼠进行治疗； 与 STING 抑制剂一起使用可预防由 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，所有三种模型都会导致肾脏中 cGAS-STING 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 肾小管将改善线粒体功能障碍、cGAS-STING 介导的炎症和与年龄相关的炎症 2) 虽然ERRs对线粒体功能调节的影响已被研究，主要是在肾脏疾病中。 与其他靶器官相比，ERR 在炎症调节中的作用是新颖的，尚未在其他靶器官中进行过研究。 为此，我们将进行机制研究，以确定 cGAS-STING 在调节中的作用。 肾脏炎症和 ERR 的影响。