Xanthine oxidoreductase in impaired diabetic wound healing.

黄嘌呤氧化还原酶在糖尿病伤口愈合受损中的作用。

• 批准号: 9138069
• 负责人: Edith Tzeng
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138069
• 关键词: Address; Affect; Amputation; Attention; Back; Biological; Biological Availability; Blood Vessels; Caring; Cell Proliferation; Clinical; Complex; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Diabetic mouse; Diabetic ulcer; Diabetic wound; Dietary Nitrite; Disease; Disease model; Dose; Endothelial Cells; Enzymes; Etiology; Event; Foot Ulcer; Foundations; Functional disorder; Generations; Goals; Half-Life; Healthcare; Healthcare Systems; Human; Hypoxia; Impaired wound healing; Impairment; Incidence; Infection; Inflammation; Injury; Intervention; Ischemia; Knockout Mice; Lead; Leg Ulcer; Lower Extremity; Mediating; Microvascular Dysfunction; Minor; Modality; Morbidity - disease rate; Mus; NADPH Oxidase; Neuropathy; Nitric Oxide; Nitric Oxide Synthase; Nitrite Reductase; Nitrites; Obesity; Organism; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Pathogenesis; Patient Care; Patients; Pharmacology; Phase I Clinical Trials; Play; Population; Predisposition; Process; Production; Property; Pulmonary Hypertension; Reactive Oxygen Species; Reporting; Research; Risk; Role; Self Care; Sickle Cell; Skin wound; Social support; Sodium Nitrite; Source; Supplementation; Testing; Therapeutic Agents; Time; Tissues; Translating; Translations; Ulcer; United States; Venous; Work; Wound Healing; XDH gene; cell injury; chronic wound; cost; diabetic; diabetic patient; diabetic wound healing; direct application; disability; genetic manipulation; healing; human tissue; improved; inhibitor/antagonist; limb amputation; mortality; mouse model; neovascularization; oxidoreductase inhibitor; productivity loss; public health relevance; restenosis; safety testing; stem; targeted treatment; vasoconstriction; wound

 DESCRIPTION (provided by applicant): Diabetes and its complications are a significant burden on the healthcare system in the United States with nearly $250 billion spent on the care of these patients in 2012. This is even more significant in the VA Healthcare System where the incidence of diabetes is three times as high. Diabetic patients are prone to develop foot and leg ulcers resulting from neuropathy, susceptibility to infection, and microvascular disease. Unfortunately, diabetics have a significantly impaired ability to heal these ulcers and often go on to minor or major limb amputations. These events lead to loss of productivity and associated morbidity and mortality. One of the deficits associated with impaired wound healing in diabetic patients is the excessive production of reactive oxygen species (ROS) and insufficient nitric oxide (NO) production. It has been demonstrated that reduction of ROS or delivery of NO to diabetic wounds can improve healing rates and reduce infection. However, NO delivery is hampered by the short half-life of the molecule and its highly reactive state. Xanthine oxidoreductase (XOR) is an enzyme known for its ability to produce ROSs and we identified that it is highly expressed in skin and wounds. XOR has attracted a great deal of attention in the past few years because it can convert the stable compound nitrite back to NO. XOR has been shown to utilize dietary nitrite to mediate the beneficial effects of NO in a variety of disease models. In the wound, preliminary data indicate that XOR plays an essential role in normal wound repair but its role in diabetic wounds remains uncertain. The systemic inhibition of XOR in diabetes appears to improve wound healing while local inhibition further delays healing. In addition, the administration of systemic or topical nitite also improves wound repair. An attractive property of XOR is that it favors the production of NO when nitrite is provided in the setting of hypoxia. When producing NO, XOR mediated ROS production is reduced. These properties are extremely favorable in the setting of chronic wounds where vascularity is diminished with resulting ischemia. In such a setting, administering nitrite may not only induce XOR to generate NO but it may also reduce ROS production. The goal of this proposal is to investigate the precise role of XOR and its products in the diabetic wound repair process. Studies will examine the function of XOR generated NO and ROS in diabetic wounds. The role of XOR in wound neovascularization will be examined to define the importance of the source of the XOR function. These studies will be aided by the use of endothelial cell specific XOR knockout mice. The proposal will culminate in examination of human wounds of different etiologies to quantify XOR activity, the ability to augment local NO production through nitrite supplementation, and the impact of other nitrite reductases in this NO production. The ultimate goal of this proposal is to establish the foundation for developing topical nitrite as a treatment for impaired diabetic wound healing. The extremely attractive aspect of such a therapy is its simplicity, low cost, and the ability to harness the body's own machinery to produce the therapeutic agent. If effective, topical nitrite therapy may also be applied to wounds of other etiologies such as venous stasis and ischemic wounds.

 描述（由申请人提供）： 糖尿病及其并发症是美国医疗保健系统的重大负担，2012 年在这些患者的护理上花费了近 2500 亿美元。这在 VA 医疗保健系统中更为重要，该系统的糖尿病发病率是美国医疗保健系统的三倍糖尿病患者容易因神经病变、感染易感性和微血管疾病而出现足部和腿部溃疡，不幸的是，糖尿病患者治愈这些溃疡的能力明显受损，并且常常会发展到小肢或大肢。这些事件导致生产力下降以及相关的发病率和死亡率，与糖尿病患者伤口愈合受损相关的缺陷之一是活性氧（ROS）产生过多和一氧化氮（NO）产生不足。研究表明，减少 ROS 或向糖尿病伤口输送 NO 可以提高愈合率并减少感染，但是，NO 的输送受到分子半衰期短及其高反应性状态的阻碍。 (XOR) 是一种以其产生 ROS 的能力而闻名的酶，我们发现它在皮肤和伤口中高度表达，在过去几年中 XOR 引起了广泛的关注，因为它可以将稳定的化合物亚硝酸盐转化回 NO。 XOR 已被证明利用膳食亚硝酸盐在多种疾病模型中介导 NO 的有益作用，初步数据表明 XOR 在正常伤口修复中发挥重要作用，但其在糖尿病伤口的全身抑制中的作用仍不确定。异或在糖尿病中，亚硝酸盐似乎可以改善伤口愈合，而局部抑制会进一步延迟愈合。此外，全身或局部施用亚硝酸盐还可以改善伤口修复，这是当在糖尿病环境中提供亚硝酸盐时，它有利于 NO 的产生。当产生 NO 时，XOR 介导的 ROS 产生会减少，这些特性对于血管供应减少并导致缺血的慢性伤口非常有利。 NO 但也可能减少 ROS 的产生，该提案的目标是研究 XOR 及其产物在糖尿病伤口修复过程中的确切作用。将检查伤口新生血管中的 XOR，以确定 XOR 功能来源的重要性。这些研究将通过使用内皮细胞特异性 XOR 敲除小鼠来帮助，该提案将最终检查不同的人类伤口。量化 XOR 活性的病因学、通过补充亚硝酸盐增加局部 NO 产生的能力以及其他亚硝酸盐还原酶在 NO 产生中的影响该提案的最终目标是为开发局部亚硝酸盐作为糖尿病受损的治疗方法奠定基础。这种疗法极具吸引力的方面是其简单、成本低，并且能够利用人体自身的机制来产生治疗剂，如果有效，局部亚硝酸盐疗法也可以应用于其他伤口。病因如静脉瘀滞和缺血性伤口。