Role of Rho Kinases in Diabetic Nephropathy

Rho 激酶在糖尿病肾病中的作用

• 批准号: 7762180
• 负责人: FARHAD R DANESH
• 金额: $ 36.32万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762180
• 关键词: Agonist; Arts; Behavior; Biochemical; Biological; Biosensor; Cell Cycle Progression; Cell Proliferation; Cell physiology; Cells; Chronic; Coronary Artery Vasospasm; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Environment; Enzymes; Erectile dysfunction; Experimental Animal Model; Experimental Models; Fibrosis; Functional disorder; Gene Expression; Gene Targeting; Generations; Genetic Transcription; Glucose; Heart failure; Hydrogen Peroxide; Hyperglycemia; Hypertension; In Vitro; Injury; Kidney; Kidney Failure; Knock-in Mouse; Knockout Mice; Laboratories; Lead; Mediating; Mitochondria; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; NADP; NADPH Oxidase; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidants; Oxidases; Oxidation-Reduction; Oxygen; Pathogenesis; Pathway interactions; Permeability; Phenotype; Play; Production; Protein-Serine-Threonine Kinases; Proteins; ROCK1 gene; Reactive Oxygen Species; Research; Rho-associated kinase; Role; Signal Pathway; Signal Transduction; Source; Stroke; Structure; Superoxides; System; Technology; Testing; Therapeutic Uses; Tissues; Transgenic Mice; Transgenic Organisms; Vesicle; base; cell motility; diabetic; fasudil; glomerulosclerosis; improved; in vivo; inhibitor/antagonist; innovation; insight; interstitial; migration; novel; novel therapeutics; promoter; public health relevance; recombinase; research study; rho GTP-Binding Proteins; stem; trafficking; transgene expression; type I and type II diabetes

DESCRIPTION (provided by applicant): Rho kinase (ROCK) is a serine/threonine protein kinase which functions as one of the downstream effectors for the small G-protein RhoA. The RhoA/ROCK pathway has an important role in mediating various cellular processes, including cytoskeletal remodeling, cell proliferation, and gene expression. More recently, the RhoA/ROCK pathway has emerged as a promising target in the treatment of coronary vasospasm, stroke, erectile dysfunction, and hypertension. In this proposal, we argue that ROCK also plays a critical role in the pathogenesis of diabetic nephropathy (DN) via its involvement in modulating the reactive oxygen species (ROS) signaling pathway. Our hypothesis is based on several novel observations: 1) RhoA/ROCK pathway is involved in glucose-induced signaling (Danesh FR et al. Proc. Natl. Acad. Sci. 2002), 2) Blockade of ROCK ameliorates progression of DN in the db/db model of type 2 diabetes (Kolavennu V et al. Diabetes 2007), and 3) our preliminary data suggesting that ROCK activation plays a pivotal role in both mitochondrial and NADPH redox signaling. Based upon these initial observations, we now propose an integrated in vitro and in vivo approach to test three specific aims. Aim 1: To test the hypothesis that at the cellular level, ROCK mediates the cross-talk between mitochondrial- and NADPH-derived ROS overproduction in the diabetic milieu. Aim 2: To test the hypothesis that selective inhibition of ROCK in the experimental models of type 1 and type 2 diabetes ameliorates the progression of DN by inhibiting ROCK-mediated ROS production. Aim 3: To test the effect of tissue-specific conditional gene targeting of ROCK in DN. The findings of this application will provide a significant advance in three aspects: first, the successful completion of this proposal is not only relevant to kidney research, but it will also provide a framework for understanding the spatial and temporal behavior of redox signaling. Second, it will assess the role of RhoA/ROCK signaling in the kidney. And third, it will lead to development of novel therapeutic strategies in DN. PUBLIC HEALTH RELEVANCE: Diabetic nephropathy remains the leading cause of renal failure in the U.S. The current study will focus on a novel pathway possibly involved in the progression of diabetic kidney disease. We propose that inhibition of the RhoA/ROCK pathway holds promise as a novel therapeutic strategy to improve microvascular outcomes in diabetes.

描述（由申请人提供）：Rho激酶（ROCK）是丝氨酸/苏氨酸蛋白激酶，其作为小G蛋白RhoA的下游效应物之一起作用。RhoA/ROCK通路在介导各种细胞过程中具有重要作用，包括细胞骨架重塑、细胞增殖和基因表达。最近，RhoA/ROCK通路已成为治疗冠状动脉血管痉挛、中风、勃起功能障碍和高血压的有希望的靶点。在本研究中，我们认为ROCK通过参与调节活性氧（ROS）信号通路在糖尿病肾病（DN）的发病机制中也起着关键作用。我们的假设是基于几个新的观察：1）RhoA/ROCK途径参与葡萄糖诱导的信号传导（Danesh FR等人，Proc.Natl. Acad. Sci. 2002），2）阻断ROCK改善了2型糖尿病db/db模型中DN的进展（Kolavennu V等人，Diabetes 2007），和3）我们的初步数据表明ROCK激活在线粒体和NADPH氧化还原信号传导中起关键作用。基于这些初步观察，我们现在提出了一个综合的体外和体内方法来测试三个特定的目标。目标1：为了检验在细胞水平上，ROCK介导糖尿病环境中线粒体和NADPH衍生的ROS过度产生之间的串扰的假设。目标二：在1型和2型糖尿病实验模型中，选择性抑制ROCK可通过抑制ROCK介导的ROS产生来改善DN的进展。目的3：检测ROCK组织特异性条件基因打靶治疗DN的效果。该应用的发现将在三个方面提供重大进展：首先，该提案的成功完成不仅与肾脏研究相关，而且还将为理解氧化还原信号的空间和时间行为提供框架。其次，它将评估RhoA/ROCK信号在肾脏中的作用。第三，它将导致DN新的治疗策略的发展。 公共卫生关系： 糖尿病肾病仍然是美国肾衰竭的主要原因。目前的研究将集中在一个新的途径可能参与糖尿病肾病的进展。我们认为抑制RhoA/ROCK通路有望成为改善糖尿病微血管结局的新治疗策略。