Mechanisms underlying impaired diabetic wound healing

描述（由申请人提供）：项目摘要/摘要伤口愈合不良是与糖尿病相关的严重并发症，并给社会造成重大损失。炎症相失调是导致糖尿病伤口愈合受损的主要因素。糖尿病患者的伤口由于炎症消退的阻碍而停滞在炎症阶段。凋亡细胞的吞噬去除是炎症消退和成功愈合的先决条件。从伤口中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手术清创期间寻求以更大规模完成的清创有点类似。在这两种情况下，目标是最大限度地减少伤口部位的死亡组织负担。我们的总体假设是基于三个相关的观察结果：（i）糖尿病小鼠和人的皮肤伤口中凋亡细胞的计数增加;（ii）从糖尿病患者收集的伤口巨噬细胞（mF）中的死细胞清除活性受损;以及iii）死细胞的成功清除充当解决炎症的信号。总之，这些观察结果导致了一个中心假设，即在糖尿病患者中，mF的凋亡细胞清除活性受损导致伤口部位凋亡细胞负荷增加。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，以加强本项目的临床相关性。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意义。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的糖尿病伤口中损伤死细胞清除中的作用;和3）检查糖化MFG-E8的功能意义，糖化MFG-E8是糖尿病伤口中由mF产生的主要死细胞识别蛋白。拟议的研究重点是新的机制，可能会解释和帮助检查糖尿病环境中的慢性炎症。重要的是，拟议的研究包括对从慢性人类伤口分离的mF进行的第一次功能研究。本研究的结果有望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。这是一位新的研究者提交的第一份提案，她是一位女性初级教师，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。项目叙述：一位新的女研究员的提议旨在测试一个创新的假设，解决对当今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。

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.