Mechanisms underlying impaired diabetic wound healing

糖尿病伤口愈合受损的机制

• 批准号: 8019532
• 负责人: Sashwati Roy
• 金额: $ 29.4万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019532
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Attenuated; Binding; Blood Circulation; Cell Count; Cells; Chronic; Complication; Cues; Debridement; Dermal; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Excision; Faculty; Failure; Glucose; Goals; Harvest; Healed; Human; Impaired wound healing; Impairment; Inflammation; Inflammatory; Laboratories; Modification; Molecular; Mus; NADPH Oxidase; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Phagocytosis; Phase; Phosphatidylserines; Process; Proteins; Recruitment Activity; Research Personnel; Resolution; Role; Signal Transduction; Site; Societies; Surgeon; Testing; Therapeutic; Tissues; Woman; Work; Wound Healing; abstracting; base; clinically relevant; cost; diabetic; diabetic patient; diabetic wound healing; glycation; granulocyte; healing; indexing; innovation; insight; macrophage; mouse model; neutrophil; novel; novel therapeutics; oxidation; wound

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.

描述（由申请人提供）：项目摘要 /抽象受损伤口愈合是与糖尿病有关的严重并发症，对社会构成了重大成本。炎症阶段失调是导致糖尿病伤口愈合损害的主要因素。糖尿病人的伤口在炎症阶段停滞不前，因为炎症的分辨率不足。吞噬细胞的吞噬清除是解决炎症和成功愈合的先决条件。伤口中死细胞的清除可能被视为细胞清创术与伤口外科医生在常规的慢性伤口手术清创术中寻求更大范围内完成的事情平行。在这两种情况下，目标是最大程度地减少伤口部位的死组织负担。我们的总体假设基于三个相关观察结果i）糖尿病小鼠和人类皮肤伤口中凋亡细胞的数量增加； （ii）从糖尿病患者中收获的伤口巨噬细胞中的死细胞清除活性损害； iii）成功清除死细胞充当a）解决炎症的信号。综上所述，这些观察结果导致了一个中心假设，即在糖尿病患者中，MF的凋亡细胞清除活性受损会导致伤口部位的凋亡细胞负担增加。反过来，这种负担延长了炎症阶段并使愈合过程变得复杂。 II型糖尿病小鼠和患者将进行研究，以增强该项目的临床相关性。已经提出了以下三个特定目标：1）测试死细胞清除率在糖尿病伤口愈合中的重要性。将检查来自II型糖尿病和II型糖尿病患者小鼠模型的伤口位点。 2）定义减弱的磷脂酰丝氨酸氧化在小鼠和人类糖尿病伤口中死细胞清除率损害中的作用； 3）检查糖化MFG-E8的功能意义，这是MF在糖尿病伤中产生的主要死细胞识别蛋白。拟议的研究集中于新的机制，这些机制将有可能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伤口分离的MF进行的首次功能研究。预计这项研究的结果将为糖尿病条件下导致伤口慢性的机制提供重要的见解，并为治疗糖尿病慢性伤口的创新治疗策略提供线索。这是一位新调查员提出的第一份提案，该提案是一名女性初级教师，试图建立一个新的实验室，重点是研究糖尿病伤口炎症的研究。项目叙述：一名新女性调查员提出的提议致力于检验一种创新的假设，以解决糖尿病性慢性伤口，这对当前社会构成了严重威胁。该项目的成功完成将提供新的治疗机会，以治疗通常与问题伤口有关的慢性炎症。

项目成果

Use of laser capture microdissection for the assessment of equine lamellar basal epithelial cell signalling in the early stages of laminitis.

使用激光捕获显微切割评估蹄叶炎早期阶段的马层状基底上皮细胞信号传导。

• DOI: 10.1111/evj.12283
• 发表时间: 2015
• 期刊: Equine veterinary journal
• 影响因子: 2.2
• 作者: Leise,BS;Watts,MR;Roy,S;Yilmaz,AS;Alder,H;Belknap,JK
• 通讯作者: Belknap,JK

Human skin wounds: a major and snowballing threat to public health and the economy.

• DOI: 10.1111/j.1524-475x.2009.00543.x
• 发表时间: 2009-11
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Sen CK;Gordillo GM;Roy S;Kirsner R;Lambert L;Hunt TK;Gottrup F;Gurtner GC;Longaker MT
• 通讯作者: Longaker MT

Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice.

• DOI: 10.1371/journal.pone.0009539
• 发表时间: 2010-03-04
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Khanna S;Biswas S;Shang Y;Collard E;Azad A;Kauh C;Bhasker V;Gordillo GM;Sen CK;Roy S
• 通讯作者: Roy S