Treatment of kidney disease in diabetes

糖尿病仍然是美国和世界各地肾脏疾病的主要原因。的 糖尿病肾病的发病机制仍然知之甚少。尽管采取了有益的干预措施 尽管在糖尿病患者中实施了减轻其一些负面影响的药物，但肾脏疾病仍在进展 在大多数患者中。最近的证据表明，线粒体动力学和功能的损害 在糖尿病肾病中起着重要作用，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。在 我们的目标是确定SIRT 3和ERR-α的机制和新的信号转导机制， 糖尿病肾病、线粒体功能障碍和足细胞损伤的预防和治疗。 在具体目标1中，我们将确定线粒体sirtuin SIRT 3如何调节糖尿病肾病， 包括通过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确定。在雄性和雌性小鼠中，i）足细胞 特异性SIRT 3敲除，或ii）SIRT 3在足细胞中的转基因过表达，或iii）用SIRT 3 iv）在SIRT 3过表达或SIRT 3激动剂处理后培养的足细胞中，我们将 确定对线粒体功能和肾脏疾病进展的影响。我们还将表演 定量磷酸蛋白质组学和乙酰组学，以确定新的信号通路，将进一步 探索与SIRT 3在肾脏中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， 包括通过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确定。在雄性和雌性小鼠中，i）足细胞 特异性ERR-α敲除，或ii）足细胞中ERR-α的转基因过表达，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 确定对线粒体功能和肾脏疾病进展的影响。我们还将表演 定量磷酸蛋白质组学和乙酰组学，以确定新的信号通路，将进一步 探索与肾脏中ERR-α效应相关的机制研究。

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.