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。这个 糖尿病肾病的发病机制尚不清楚。尽管进行了有益的干预 在糖尿病患者中实施，以减轻其一些负面影响，肾脏疾病仍在进展 在这些患者中的大多数。最近的证据表明，线粒体动力学和功能的损害 在糖尿病肾病中扮演重要角色，并为改善治疗策略带来希望 线粒体功能和可能预防或减缓肾脏疾病进展的相关途径。在……里面 我们的目标是确定SIRT3和ERR-α的作用机制和新的信号机制。 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是如何调节糖尿病肾病的， 包括通过调节线粒体的功能和动力学，以及激活新的信号通路 由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有i)足细胞 特异性SIRT3基因敲除，或II)SIRT3在足细胞中的转基因过表达，或III)经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 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确定新的信号通路将进一步 探索与肾脏中SIRT3作用相关的机制研究。 在特定的目标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的功能和动力学，以及激活新的信号通路 由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有i)足细胞 特定的Err-α敲除，或ii)在足细胞中转基因过表达Err-α，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 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.