Mechanisms underlying impaired diabetic wound healing

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，并对 社会。炎症时相失调是导致糖尿病损害的主要因素 伤口愈合。糖尿病人的伤口处于炎症阶段是因为 消退炎症。吞噬细胞清除凋亡细胞是解决 发炎和成功愈合。从伤口中清除死亡细胞可以被看作是细胞 清创手术在一定程度上与伤口外科医生试图在更大范围内实现的目标有些相似 慢性创面的常规清创手术。在这两种情况下，目标都是将死亡组织的负担降至最低 从伤口处找到的。我们的总体假设基于三个相关的观察结果：i)计数增加 糖尿病小鼠和人类皮肤伤口中的凋亡细胞；(Ii)损害死亡细胞清除活性 创伤巨噬细胞(m？)从糖尿病患者身上收获；以及iii)死亡细胞的成功清除起到了 ？消炎的信号。综上所述，这些观察结果导致了一个中心假设，即在 糖尿病患者凋亡细胞清除活性受损的m？结果导致细胞凋亡负荷增加 伤口处。这一负担反过来又延长了炎症阶段，并使愈合过程复杂化。第II类 将对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。这个 已经提出了以下三个具体目标：1)测试糖尿病患者死亡细胞清除的意义 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细胞将被 研究；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 3)检测糖化的MFG-E8的功能意义，糖化的MFG-E8是主要的 M？产生死亡细胞识别蛋白。在糖尿病伤口上。拟议的研究集中在小说上。 ？潜在地解释和帮助控制糖尿病环境中的慢性炎症的机制。重要的是 拟议的研究包括将对m？进行的首批功能研究。从慢性人类中分离出来 伤口。这项研究的结果有望对导致创伤的机制提供关键的见解。 糖尿病条件下的慢性化，并为创新的治疗策略提供线索 糖尿病慢性伤口。这是一名初级女性调查员提交的第一份提案。 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。项目叙事 一位新的女性研究员提出的这项建议旨在测试一种创新的假说 糖尿病慢性创面，对当前社会构成严重威胁。项目圆满完成 将提供新的治疗机会来治疗慢性炎症，这种炎症通常与 有问题的伤口。

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.