Mechanisms underlying impaired diabetic wound healing

糖尿病伤口愈合受损的机制

• 批准号: 8004785
• 负责人: Sashwati Roy
• 金额: $ 0.93万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-23 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004785
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Attenuated; Binding; Blood Circulation; Cell Count; Cells; Chronic; Complication; Cues; Debridement; Dermal; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Excision; Faculty; Failure; Glucose; Goals; Harvest; Healed; Human; Impaired wound healing; Impairment; Inflammation; Inflammatory; Laboratories; Modification; Molecular; Mus; NADPH Oxidase; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Patients; Phagocytosis; Phase; Phosphatidylserines; Process; Proteins; Recruitment Activity; Research Personnel; Resolution; Role; Signal Transduction; Site; Societies; Surgeon; Testing; Therapeutic; Tissues; Woman; Work; Wound Healing; abstracting; base; clinically relevant; cost; diabetic; diabetic patient; diabetic wound healing; glycation; granulocyte; healing; indexing; innovation; insight; macrophage; mouse model; neutrophil; novel; novel therapeutics; oxidation; wound

Project Summary / Abstract Impaired wound healing is a serious complication associated with diabetes and poses a major cost to the society. Dysregulated inflammatory phase is a major factor that contributes to the impairment of diabetic wound healing. Diabetic human wound are stalled at the inflammatory phase because of insufficiencies in the resolution of inflammation. Phagocytic removal of apoptotic cells is a pre-requisite for the resolution of inflammation and successful healing. The clearance of dead cells from wounds may be viewed as ¿cellular debridement¿ somewhat parallel to what the wound surgeon seeks to accomplish on a larger scale during routine surgical debridement of chronic wounds. In both cases, the goal is to minimize burden of dead tissue from the wound site. Our overall hypothesis is based on three related observations i) increased count of apoptotic cells in dermal wounds of diabetic mice and humans; (ii) compromised dead cell clearance activity in wound macrophages (m?) harvested from diabetics; and iii) that successful clearance of dead cells act as a ? signal to resolve inflammation. Taken together, these observations led to the central hypothesis that in diabetics, impairment of apoptotic cell clearance activity of m? results in increased apoptotic cell burden at the wound site. This burden, in turn, prolongs the inflammatory phase and complicates the healing process. Type II diabetic mice and patients will be investigated in tandem to strengthen clinical relevance of this project. The following three specific aims have been proposed: 1) test the significance of dead cell clearance in diabetic wound healing. Wound-site cells from a mouse model of type II diabetes and type II diabetic patients will be examined; 2) define the role of attenuated phosphatidylserine oxidation in impairment of dead cell clearance in diabetic wounds of mice and humans; and 3) examine the functional significance of glycated MFG-E8, a major dead cell recognition protein produced by m? in diabetic wounds. The proposed studies focus on novel ? mechanisms that will potentially explain and help check chronic inflammation in a diabetes setting. Importantly, the proposed studies include first functional studies to be performed on m? isolated from chronic human wounds. Results of this study are expected to provide key insight into the mechanisms that result in wound chronicity under conditions of diabetes and to provide cues for innovative therapeutic strategies to treat diabetic chronic wounds. This is the first proposal submitted by a new investigator who is a woman junior faculty seeking to establish a new laboratory focusing long-term on the study of diabetic wound inflammation. Project Narrative The proposal by a new woman investigator is directed towards testing an innovative hypothesis addressing diabetic chronic wounds which poses serious threat to the current society. Successful completion of the project will offer novel therapeutic opportunities to treat chronic inflammation that is commonly associated with problem wounds.

项目概要/摘要 伤口愈合受损是与糖尿病相关的严重并发症，给患者带来重大损失 炎症阶段失调是导致糖尿病损害的一个主要因素。 糖尿病人的伤口由于炎症阶段而停滞不前。 吞噬细胞清除凋亡细胞是消退炎症的先决条件。 炎症和伤口中死亡细胞的成功愈合可以被视为 ¿细胞的 碎片??有点类似于伤口外科医生在更大范围内寻求完成的任务 在这两种情况下，对慢性伤口进行常规清创手术的目的是尽量减少坏死组织的负担。 我们的总体假设基于三个相关的观察 i) 增加的数量 糖尿病小鼠和人类皮肤伤口中的凋亡细胞；(ii) 死亡细胞清除活性受损； 从糖尿病患者身上采集的伤口巨噬细胞（m？）；以及 iii）成功清除死亡细胞 总而言之，这些观察结果得出了一个中心假设： 糖尿病患者中，m? 的凋亡细胞清除活性受损会导致细胞凋亡负担增加。 这种负担反过来又会延长炎症期并使 II 型愈合过程复杂化。 糖尿病小鼠和患者将同时进行研究，以加强该项目的临床相关性。 提出了以下三个具体目标：1）测试死细胞清除在糖尿病患者中的重要性 来自 II 型糖尿病小鼠模型和 II 型糖尿病患者的伤口愈合细胞将被用于治疗伤口愈合。 2) 确定减弱的磷脂酰丝氨酸氧化在损伤死细胞清除中的作用 小鼠和人类的糖尿病伤口；3) 检查糖化 MFG-E8 的功能意义，这是一种主要成分。 糖尿病伤口中 m? 产生的死细胞识别蛋白。 ？可能解释和帮助检查糖尿病环境中的慢性炎症的机制。 拟议的研究包括对从慢性人类中分离出的 m? 进行的首次功能研究。 这项研究的结果有望为导致伤口的机制提供重要见解。 糖尿病条件下的慢性病，​​并为治疗的创新治疗策略提供线索 这是一位女青年新研究者提交的第一份提案。 教师寻求建立一个新的实验室，长期专注于糖尿病伤口炎症的研究。 一位新女性调查员的提议旨在测试一个创新假设，解决 糖尿病慢性伤口对当前社会构成严重威胁。 将为治疗通常与以下疾病相关的慢性炎症提供新的治疗机会 问题伤口。