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Redox regulation of endothelial function and wound healing

内皮功能和伤口愈合的氧化还原调节

基本信息

批准号：
7626778
负责人：
Alex F Chen
金额：
$ 26.96万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7626778
关键词：
Address Adenoviruses Affect Autologous Blood Vessels Bone Marrow Cell Therapy Cell physiology Cells Clinical Complex Crackles Cutaneous Data Defect Diabetes Mellitus Diabetic Angiopathies Diabetic Neuropathies Diabetic mouse Diabetic wound Effectiveness Electron Transport Endothelial Cells Enzymes Erinaceidae Exhibits Functional disorder GTP Cyclohydrolase I Gene Transfer Generations Genetic Goals Harvest Healed Home environment Hyperglycemia Impaired wound healing Impairment In Vitro Insulin-Dependent Diabetes Mellitus Intervention Knockout Mice Knowledge Laboratories Lead Left Limb Salvage Link Manganese Superoxide Dismutase Mediating Mediator of activation protein Mitochondria Modification Mus Nitric Oxide Oxidation-Reduction Oxidative Stress Play Principal Investigator Publishing Reactive Oxygen Species Refractory Regulation Research Research Personnel Resistance Role Signaling Molecule Site Stem cells Streptozocin Superoxides Systems Biology Testing Thick Time Topical application Transgenic Mice Treatment Protocols Work Wound Healing angiogenesis cell type cofactor diabetic diabetic patient diabetic wound healing expectation extracellular gene therapy genetic manipulation healing human NOS3 protein improved in vivo morphogens neovascularization novel overexpression oxidative damage programs repaired tetrahydrobiopterin type I diabetic wound

项目摘要

DESCRIPTION (provided by applicant): Wound healing impairment in diabetic patients represents a particular challenging clinical problem to which no efficacious treatment regimens exist. Endothelial cell dysfunction is a significant contributor to impaired wound healing. A cardinal feature of endothelial dysfunction in diabetes is hyperglycemia- mediated superoxide anion overproduction by the mitochondrial electron transport chain with resultant oxidative stress. Our preliminary data suggest that increased superoxide in diabetes appears to impair the functions of three endothelial factors on wound healing - tetrahydrobiopterin (BH4) and endothelial nitric oxide synthase (eNOS), endothelial morphogen sonic hedgehog (SHH), and endothelial progenitor cells (EPCs). Yet remarkably little is known about how superoxide-induced oxidative stress regulates these factors central to wound repair. Such knowledge is critical for successfully modulating endothelial function to improve wound healing in diabetes. For example, discovery of the defects in diabetic EPC and the means to correct them could lead to autologous cell therapies for diabetic wounds. This project will focus on oxidative stress-induced endothelial dysfunction in diabetic wound repair, thus filling a significant gap in such knowledge. We hypothesize that oxidative stress in diabetic wounds is a common cause for the dysfunction of the three repair mediators - eNOS, sonic hedgehog and endothelial progenitor cells, resulting in impaired healing. To test this hypothesis, we will pursue three specific aims using streptozotocin-induced type 1 diabetic mice. In aim 1, we will determine how oxidative stress impairs cutaneous eNOS function, focusing on the role of its essential cofactor BH4. In Aim 2, we will determine the mechanism through which sonic hedgehog regulates diabetic wound healing under oxidative stress. In Aim 3, we will determine how endothelial progenitor cells become dysfunctional in type 1 diabetes. The major significance of the proposed studies is that it will for the first time determine how superoxide regulates endothelial function and wound repair in an integrated fashion, which may provide new knowledge regarding an interconnected mechanism that affects wound healing in type 1 diabetes, thus addressing a fundamental issue in system biology and pathophysiology of wound healing.

描述（由申请方提供）：糖尿病患者的伤口愈合障碍是一个特别具有挑战性的临床问题，目前尚无有效的治疗方案。内皮细胞功能障碍是伤口愈合受损的重要因素。糖尿病内皮功能障碍的一个主要特征是高血糖介导的线粒体电子传递链超氧阴离子过量产生，导致氧化应激。我们的初步数据表明，糖尿病中超氧化物的增加似乎会损害三种内皮因子对伤口愈合的功能-四氢生物蝶呤（BH 4）和内皮一氧化氮合酶（eNOS），内皮形态发生蛋白音刺猬（SHH）和内皮祖细胞（EPC）。然而，关于超氧化物诱导的氧化应激如何调节这些对伤口修复至关重要的因素，人们知之甚少。这些知识对于成功调节内皮功能以改善糖尿病伤口愈合至关重要。例如，发现糖尿病EPC中的缺陷以及纠正它们的方法可能导致糖尿病伤口的自体细胞疗法。该项目将重点关注糖尿病伤口修复中氧化应激诱导的内皮功能障碍，从而填补了此类知识的重大空白。我们假设糖尿病伤口中的氧化应激是导致三种修复介质- eNOS、音刺猬和内皮祖细胞功能障碍的常见原因，从而导致愈合受损。为了验证这一假设，我们将使用链脲佐菌素诱导的1型糖尿病小鼠追求三个特定的目标。在目标1中，我们将确定氧化应激如何损害皮肤eNOS功能，重点是其重要辅因子BH 4的作用。在目标2中，我们将确定在氧化应激下，音刺猬调节糖尿病伤口愈合的机制。在目标3中，我们将确定内皮祖细胞在1型糖尿病中是如何变得功能障碍的。拟议研究的主要意义在于，它将首次确定超氧化物如何以综合方式调节内皮功能和伤口修复，这可能会提供有关影响1型糖尿病伤口愈合的相互关联机制的新知识，从而解决伤口愈合的系统生物学和病理生理学中的基本问题。