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: 10154246
• 负责人: MOSHE LEVI
• 金额: $ 49.39万
• 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/10154246
• 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; 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/antagonist; 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注射增加的假设 介导与年龄有关的肾脏疾病。我们建议增加与雌激素相关的接收器ERRα的表达 ERRγ提高了线粒体功能，并降低CGAS插曲信号传导，细胞感应和 炎症，逆转与年龄有关的肾脏疾病。另外，错误对感应的影响， 炎症和纤维化取决于CGAS。此外，ERRα和ERRγ的表达增加 或抑制CGAS-丁基信号传导可防止叶酸，LPS或 缺血/再灌注 在特定目的1中，我们将测试肾小管ERRα或ERRγ增加的假设 线粒体功能和炎症以及与年龄相关的肾脏疾病。我们将确定：a） 肾小管ERRα或ERRγ或简单ERRα/ERRγ的影响增加了肾脏的表达 线粒体功能，注射和肾脏疾病； b）如果肾小管增加错误，则可以防止急性 A）叶酸，B）LPS或C）缺血/再灌注介导的肾损伤。这些研究的理由是 这三个模型都导致儿童的ERRα和ERRγ表达降低。 c）增加的直接影响 在人近端结核细胞中ERRα，ERRγ或ERRγ的表达。 在特定目标2中，我们将测试以下假设，即ERRα或ERRγ对反向炎症的影响 衰老中的肾脏疾病是通过CGAS插入依赖机制介导的。我们将确定 A）CGA的作用：用ERR处理的广义或肾脏特异性CGA敲除小鼠； b）sting： 用ERR治疗的广义或肾脏特异性刺激敲除小鼠； c）我们将确定小鼠的治疗是否 用sting抑制剂可防止由A）叶酸，B）LPS或C）缺血/再灌注介导的急性肾脏损伤。 这些研究的理由是，所有三个模型都会导致儿童CGAS刺激的表达增加。 创新：1）这些研究将确定诱导的ERR-α和ERR-γ是否增加 肾小管将改善线粒体功能障碍，CGAS插入介导和与年龄有关 肾脏疾病。 2）虽然错误在线粒体功能调节中的影响已经研究了，但主要是 其他目标器官，错误在炎症调节中的影响是新颖的，尚未在 肾。为此，我们将进行机械研究，以确定CGAS插入在调节中的作用 炎症和肾脏中ERR的影响。