Mechanisms underlying impaired diabetic wound healing

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，并且对糖尿病患者造成重大损失。 社会炎症时相失调是导致糖尿病性视网膜病变损害的主要因素。 伤口愈合糖尿病患者的伤口在炎症阶段停滞，这是因为 炎症消退。凋亡细胞的吞噬去除是解决细胞凋亡的先决条件。 炎症和成功愈合。从伤口中清除死细胞可以被视为细胞的 清创术在某种程度上类似于伤口外科医生在手术期间寻求在更大范围内完成的手术。 慢性伤口的常规外科清创术。在这两种情况下，目标是最大限度地减少死亡组织的负担 从伤口处我们的总体假设是基于三个相关的观察i）增加计数 糖尿病小鼠和人的皮肤伤口中的凋亡细胞;（ii）糖尿病小鼠和人的皮肤伤口中的死亡细胞清除活性受损。 伤口巨噬细胞（m？）从糖尿病患者中收集;和iii）死亡细胞的成功清除作为 ?缓解炎症的信号。综上所述，这些观察结果导致了一个中心假设， 糖尿病患者，M？导致凋亡细胞负荷增加， 伤口部位这种负担，反过来，延长炎症阶段，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。的 本研究提出了以下三个具体目标：1）检测糖尿病患者死亡细胞清除率的意义。 伤口愈合来自II型糖尿病小鼠模型和II型糖尿病患者的伤口部位细胞将被移植到 2）确定减弱的磷脂酰丝氨酸氧化在损伤死亡细胞清除中的作用， 小鼠和人类的糖尿病伤口;和3）检查糖化MFG-E8的功能意义，这是一个主要的 死亡细胞识别蛋白由M？在糖尿病伤口中。建议的研究集中在小说 ?这些机制可能解释并帮助检查糖尿病环境中的慢性炎症。重要的是， 拟议的研究包括第一次功能性研究将在M？分离自慢性人类 伤口这项研究的结果预计将提供关键的洞察机制，导致伤口 慢性糖尿病的条件下，并提供线索，创新的治疗策略，以治疗 糖尿病慢性伤口这是一名新调查员提交的第一份提案， 学院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 一位新的女调查员提出的建议旨在检验一个创新的假设， 糖尿病慢性创面对当今社会构成严重威胁。成功完成项目 将为治疗慢性炎症提供新的治疗机会， 问题伤口

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.