Dual Oxidase 2 as a New Target for Treatment of Diabetic Nephropathy

双氧化酶2作为糖尿病肾病治疗新靶点

基本信息

批准号：
10624760
负责人：
Bridget M Ford
金额：
$ 13.55万
依托单位：
UNIVERSITY OF THE INCARNATE WORD
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-19 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624760
关键词：
Activator Appliances Apoptosis Biochemical Biomedical Research Calcium Calcium-Binding Domain Cells Data Development Diabetes Mellitus Diabetic Nephropathy EF Hand Motifs Education Environment Enzymes Epithelial Cells Event Family Foot Process Freezing General Population Generations Glucose Goals High Fat Diet Hydrogen Peroxide Hyperglycemia Immunohistochemistry Impairment In Vitro Infrastructure Injury Integral Membrane Protein Intervention Kidney Kidney Diseases Knockout Mice Lesion Mediating Mediator Medical Membrane Molecular Morbidity - disease rate Morphology Mus N-terminal NADPH Oxidase Nature Non-Insulin-Dependent Diabetes Mellitus Nox enzyme Oxidants Oxidases Oxidative Stress Oxidative Stress Induction Pathogenesis Pathologic Pathology Patients Peroxidases Play Proteins Reactive Oxygen Species Regulation Renal function Renin-Angiotensin System Research Role Source Stress Superoxides System Testing Therapeutic Agents Therapeutic Intervention Thyroid Gland Thyroid Hormones Tissues Translating Transmembrane Domain Universities Up-Regulation Western Blotting Wild Type Mouse antioxidant therapy cell injury design diabetic euglycemia experience experimental study extracellular hormone biosynthesis in vivo kidney cortex member non-diabetic novel novel therapeutic intervention pharmacologic phase II trial podocyte prevent protein expression public health relevance slit diaphragm stem subcellular targeting targeted treatment type I and type II diabetes underrepresented minority student

项目摘要

Project Summary/Abstract Glomerular epithelial cell/podocyte injury is a prominent pathological feature of diabetic nephropathy (DN). In podocytes, hyperglycemia causes alteration of slit diaphragm proteins, foot process effacement, apoptosis and cell detachment, events that ultimately results in loss of renal function. High glucose concentrations (HG) and oxidative stress are potential mediators of glomerular injury in diabetes. We have evidence that Dual oxidase 2 (Duox2) is expressed in glomerular cells and contributes to HG-induced reactive oxygen species (ROS) generation as well as podocyte injury. Additionally, we have demonstrated that glomeruli isolated from DuoxA-/- mice were protected from high glucose-induced hydrogen peroxide generation. The central hypothesis of this proposal is that the ROS generated by Duox2 play a pivotal role in glomerular lesions and podocyte injury in the diabetic kidney. The goals of this proposal are to utilize in vitro and in vivo approaches to establish the importance of Duox2 in podocyte injury in the diabetic environment and identify the factors that are modulating Duox2 activity/expression. The role of Duox activators (DuoxA), translational mechanisms, and calcium in Duox2 activation will be explored. For the in vivo studies, we will utilize previously collected kidney cortices from diabetic and non-diabetic mice where DuoxA function is impaired. As no data related to Duox enzyme expression and function within podocytes are available, the experiments proposed should serve as proof of concept to demonstrate the utility of targeting the Duox/DuoxA system to reduce diabetes-mediated glomerular lesions. Characterization of the deleterious actions of Duox2 and identification of its regulators will contribute to the design of novel therapeutic interventions and will help establish adjunct therapy to treat DN. The studies will stress the relevance of the development of modulators of Duox2 expression and activity in the kidney as therapeutic agents to prevent or reverse DN. Furthermore, this proposal will enhance the research and educational infrastructure at the University of the Incarnate Word, introducing biomedical research experiences to underrepresented minority students who would otherwise lack such opportunities.

项目概要/摘要肾小球上皮细胞/足细胞损伤是糖尿病肾病的突出病理特征（DN）。在足细胞中，高血糖会导致裂隙隔膜蛋白、足突的改变消失、细胞凋亡和细胞脱离，这些事件最终导致肾功能丧失。高的葡萄糖浓度（HG）和氧化应激是肾小球损伤的潜在介质糖尿病。我们有证据表明双氧化酶 2 (Duox2) 在肾小球细胞中表达并且有助于 HG 诱导的活性氧 (ROS) 产生以及足细胞损伤。此外，我们还证明从 DuoxA-/- 小鼠中分离的肾小球受到保护高葡萄糖诱导过氧化氢的产生。该提案的中心假设是 Duox2产生的ROS在糖尿病肾小球病变和足细胞损伤中发挥关键作用肾。该提案的目标是利用体外和体内方法来建立 Duox2 在糖尿病环境中足细胞损伤中的重要性，并确定影响因素调节 Duox2 活性/表达。 Duox 激活剂 (DuoxA) 的作用、翻译机制、将探讨钙在 Duox2 激活中的作用。对于体内研究，我们将利用之前收集了 DuoxA 功能受损的糖尿病和非糖尿病小鼠的肾皮质。由于没有与足细胞内 Duox 酶表达和功能相关的数据可用，实验提议应作为概念证明来证明针对 Duox/DuoxA 的实用性系统以减少糖尿病介导的肾小球病变。有害行为的特征 Duox2 及其调节因子的鉴定将有助于新型治疗干预措施的设计并将有助于建立治疗 DN 的辅助疗法。研究将强调相关性开发肾脏中 Duox2 表达和活性的调节剂作为治疗剂预防或逆转 DN。此外，该提案将加强研究和教育化身世界大学的基础设施，将生物医学研究经验介绍给少数族裔学生代表性不足，否则他们将缺乏这样的机会。