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. ? ? ?
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