Mechanisms underlying impaired diabetic wound healing

描述(由申请人提供)：项目摘要/摘要创面愈合受损是与糖尿病相关的严重并发症，对社会造成重大损失。炎症时相调节失调是糖尿病创面愈合障碍的主要原因。糖尿病人的伤口由于炎症消退不充分而停滞在炎症阶段。吞噬细胞清除凋亡细胞是消退炎症和成功愈合的先决条件。从伤口中清除死亡细胞可以被视为与伤口外科医生在慢性伤口常规外科清创过程中寻求更大规模的细胞清创多少是平行的。在这两种情况下，目标都是将伤口处死亡组织的负担降至最低。我们的总体假设基于三个相关的观察结果：1)糖尿病小鼠和人类皮肤创面的凋亡细胞数量增加；(2)糖尿病患者伤口巨噬细胞(MF)的死亡细胞清除活性受损；以及3)死亡细胞的成功清除起到了消炎信号的作用。综上所述，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会导致创面部位的凋亡细胞负担增加。这一负担反过来又延长了炎症阶段，并使愈合过程复杂化。将对II型糖尿病小鼠和患者进行联合研究，以加强该项目的临床相关性。提出了以下三个具体目标：1)检测死亡细胞清除在糖尿病创面愈合中的意义。2)确定减弱的磷脂酰丝氨酸氧化在糖尿病小鼠和人类糖尿病伤口的死亡细胞清除受损中的作用；以及3)检测糖化的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亡细胞识别蛋白。拟议的研究重点放在新的机制上，这些机制将潜在地解释和帮助控制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体伤口分离的MF进行的第一次功能研究。这项研究的结果有望为糖尿病条件下创面慢性化的机制提供关键的见解，并为治疗糖尿病慢性创面的创新治疗策略提供线索。这是由一位女性初级教员提交的第一份提案，她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。项目简介：由一位新的女性研究员提出的建议旨在测试一种针对糖尿病慢性伤口的创新假说，这种伤口对当前社会构成严重威胁。该项目的成功完成将为治疗通常与问题伤口有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.