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：
7234132
负责人：
Alex F Chen
金额：
$ 23.88万
依托单位：
MICHIGAN STATE UNIVERSITY
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/7234132
关键词：
Address Adenoviruses Affect Autologous Blood Vessels Bone Marrow Cell Therapy Cell physiology Cells Clinical Closure 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 Patients Play Principal Investigator Protein Overexpression Publishing Rate 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 wound healing expectation extracellular gene therapy genetic manipulation healing human NOS3 protein improved in vivo morphogens neovascularization novel 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（由申请人提供）：糖尿病患者的伤口愈合障碍代表了一个特殊的具有挑战性的临床问题，对此不存在有效的治疗方案。内皮细胞功能障碍是伤口愈合受损的重要原因。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过度产生超氧阴离子，从而产生氧化应激。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（BH4）和内皮一氧化氮合酶（eNOS）、内皮形态发生素音刺猬（SHH）和内皮祖细胞（EPC）。然而，人们对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 的缺陷以及纠正这些缺陷的方法可能会导致糖尿病伤口的自体细胞疗法。该项目将重点研究糖尿病伤口修复中氧化应激诱导的内皮功能障碍，从而填补此类知识的重大空白。我们推测，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。为了检验这一假设，我们将使用链脲佐菌素诱导的 1 型糖尿病小鼠来追求三个特定目标。在目标 1 中，我们将确定氧化应激如何损害皮肤 eNOS 功能，重点关注其必需辅助因子 BH4 的作用。在目标 2 中，我们将确定 sonic hedgehog 在氧化应激下调节糖尿病伤口愈合的机制。在目标 3 中，我们将确定 1 型糖尿病中内皮祖细胞如何变得功能障碍。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的基本问题。