Mechanisms underlying impaired diabetic wound healing

糖尿病伤口愈合受损的机制

• 批准号: 7580899
• 负责人: Sashwati Roy
• 金额: $ 30万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7580899
• 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

DESCRIPTION (provided by applicant): 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 (mF) 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 mF 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 mF 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 mF 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.

描述（由申请人提供）： 项目摘要/摘要 伤口愈合受损是与糖尿病相关的严重并发症，给社会带来重大损失。炎症阶段失调是导致糖尿病伤口愈合受损的主要因素。由于炎症消退不足，糖尿病人的伤口停滞在炎症阶段。吞噬细胞清除凋亡细胞是解决炎症和成功愈合的先决条件。从伤口清除死细胞可以被视为细胞清创，这与伤口外科医生在慢性伤口的常规外科清创期间寻求更大规模地完成的任务有些相似。在这两种情况下，目标都是尽量减少伤口部位死亡组织的负担。我们的总体假设基于三个相关的观察结果：i）糖尿病小鼠和人类皮肤伤口中凋亡细胞的数量增加； (ii) 从糖尿病患者身上采集的伤口巨噬细胞 (mF) 的死细胞清除活性受损； iii) 成功清除死细胞可作为解决炎症的信号。总而言之，这些观察结果得出了一个中心假设：在糖尿病患者中，mF 凋亡细胞清除活性受损会导致伤口部位凋亡细胞负担增加。这种负担反过来又会延长炎症阶段并使愈合过程复杂化。 II 型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伤口愈合中的重要性。将检查来自 II 型糖尿病小鼠模型和 II 型糖尿病患者的伤口部位细胞； 2) 确定减弱的磷脂酰丝氨酸氧化在小鼠和人类糖尿病伤口死细胞清除受损中的作用； 3) 检查糖化 MFG-E8 的功能意义，MFG-E8 是 mF 在糖尿病伤口中产生的一种主要死细胞识别蛋白。拟议的研究重点关注可能解释和帮助检查糖尿病环境中慢性炎症的新机制。重要的是，拟议的研究包括对从人类慢性伤口中分离出的 mF 进行的首次功能研究。这项研究的结果预计将为糖尿病条件下导致伤口慢性化的机制提供关键见解，并为治疗糖尿病慢性伤口的创新治疗策略提供线索。这是一位新研究者提交的第一份提案，她是一名女性初级教员，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。项目叙述：一位新女性研究员的提案旨在测试一项创新假设，解决对当前社会构成严重威胁的糖尿病慢性伤口。该项目的成功完成将为治疗通常与问题伤口相关的慢性炎症提供新的治疗机会。