Treatment of kidney disease in diabetes

糖尿病肾病的治疗

• 批准号: 9884758
• 负责人: MOSHE LEVI
• 金额: $ 35.17万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884758
• 关键词: Agonist; Biogenesis; Cell Culture Techniques; Deacetylation; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Diet; Disease; ERR1 protein; Female; Fibrosis; Funding; G-Protein-Coupled Receptors; GPBAR1 gene; Glucose; Human; Impairment; Injury; Intervention; Kidney; Kidney Diseases; Knock-out; Label; Mediating; Microscopy; Mitochondria; Mitochondrial Proteins; Mus; NADH; Nuclear; Nuclear Receptors; Obese Mice; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Prevention; Renal function; Resolution; Rodent; Role; Signal Pathway; Signal Transduction; Sirtuins; Techniques; Testing; Transgenic Organisms; Translating; Up-Regulation; db/db mouse; diabetic; improved; in vivo; innovation; male; mitochondrial dysfunction; mouse model; novel; novel therapeutic intervention; overexpression; phosphoproteomics; podocyte; prevent; treatment strategy

Diabetes continues to be the leading causes of kidney disease in the U.S. and around the world. The pathogenesis of diabetic kidney disease remains poorly understood. Despite beneficial interventions implemented in patients with diabetes that mitigate some of its negative effects, kidney disease still progresses in most of these patients. Recent evidence indicates that impairments in mitochondrial dynamics and function plays an important role in diabetic kidney disease and brings promise to treatment strategies for improving mitochondrial function and the related pathways that may prevent or slow the progression of kidney disease. In this proposal, we aim to determine the mechanisms and novel signaling mechanisms of SIRT3 and ERR-α in the prevention and treatment of diabetic kidney disease, mitochondrial dysfunction, and podocyte injury. In Specific Aim 1, we will determine how the mitochondrial sirtuin SIRT3 modulates diabetic kidney disease, including by regulating mitochondrial function and dynamics, and activating novel signaling pathways determined by quantitative phosphoproteomics and acetylomics. In male and female mice with i) podocyte specific SIRT3 knockout, or ii) transgenic overexpression of SIRT3 in podocytes, or iii) treated with a SIRT3 agonist, or iv) in podocytes grown in culture following SIRT3 overexpression or SIRT3 agonist treatment we will determine the effects on mitochondrial function and progression of kidney disease. We will also perform quantitative phosphoproteomics and acetylomics to determine novel signaling pathways that will be further explored for mechanistic studies related to SIRT3 action in the kidney. In Specific Aim 2, we will determine how the nuclear receptor ERR-α modulates diabetic kidney disease, including by regulating mitochondrial function and dynamics, and activating novel signaling pathways determined by quantitative phosphoproteomics and acetylomics. In male and female mice with i) podocyte specific ERR-α knockout, or ii) transgenic overexpression of ERR-α in podocytes, or iii) treated with a ERR-α agonist, or iv) in podocytes grown in culture following ERR-α overexpression or ERR-α agonist we will determine the effects on mitochondrial function and progression of kidney disease. We will also perform quantitative phosphoproteomics and acetylomics to determine novel signaling pathways that will be further explored for mechanistic studies related to ERR-α effects in the kidney.

糖尿病仍然是美国和世界各地肾脏疾病的主要原因。 尽管采取了有益的干预措施，但对糖尿病肾病的发病机制仍知之甚少。 在糖尿病患者中实施可减轻其一些负面影响，但肾脏疾病仍在进展 最近的证据表明，在大多数此类患者中，线粒体动力学和功能受损。 在糖尿病肾病中发挥着重要作用，并为改善糖尿病肾病的治疗策略带来了希望 线粒体功能和相关途径可以预防或减缓肾脏疾病的进展。 本提案的目的是确定 SIRT3 和 ERR-α 的机制和新的信号传导机制 预防和治疗糖尿病肾病、线粒体功能障碍和足细胞损伤。 在具体目标 1 中，我们将确定线粒体 Sirtuin SIRT3 如何调节糖尿病肾病， 包括调节线粒体功能和动力学，以及激活新的信号通路 通过定量磷酸蛋白质组学和乙酰组学测定具有 i) 足细胞的雄性和雌性小鼠。 特异性 SIRT3 敲除，或 ii) 足细胞中 SIRT3 转基因过度表达，或 iii) 用 SIRT3 处理 激动剂，或 iv) 在 SIRT3 过表达或 SIRT3 激动剂治疗后培养的足细胞中，我们将 我们还将确定对线粒体功能和肾脏疾病进展的影响。 磷酸蛋白质组学和乙酰组学以确定新的信号通路，这将进一步 探索与 SIRT3 在肾脏中的作用相关的机制研究。 在具体目标 2 中，我们将确定核受体 ERR-α 如何调节糖尿病肾病， 包括调节线粒体功能和动力学，以及激活新的信号通路 通过定量磷酸蛋白质组学和乙酰组学测定具有 i) 足细胞的雄性和雌性小鼠。 特异性 ERR-α 敲除，或 ii) 足细胞中 ERR-α 转基因过度表达，或 iii) 用 ERR-α 处理 激动剂，或 iv) 在 ERR-α 过表达或 ERR-α 激动剂后培养的足细胞中，我们将 我们还将确定对线粒体功能和肾脏疾病进展的影响。 磷酸蛋白质组学和乙酰组学以确定新的信号通路，这将进一步 探索与肾脏中 ERR-α 效应相关的机制研究。