Cellular / Molecular Biology of Inflammation and Repair

伤情描述(逐字摘录自申请人摘要)及其处理 仍然是外科手术的中流砥柱。糖尿病、血管疾病的异常修复 疾病、营养不良、感染和其他临床状况挑战着 从业者，并消耗相当大一部分医疗保健费用。这个 本项目的重点仍然是细胞和分子的研究。 生物学的正常组织修复，是基于一个充分的前提 对正常伤口愈合的了解将为 异常修复的临床干预。具体目标是由 从过去的投资中挑选出最有潜力扩大 对炎症和修复调节的机械性理解。那些 观察和具体目标是：1)创面来源的巨噬细胞活跃 诱导伤口多形核白细胞(PMN)凋亡 效应器机制，至少包括b3整合素和 巨噬细胞表面膜结合型肿瘤坏死因子-a。建议进行的实验 具体目标我将通过研究以下内容来扩展这些改变范式的观察 肿瘤坏死因子-α及其受体在修复中的作用 巨噬细胞依赖的中性粒细胞凋亡机制。2)诱导型一氧化氮 合酶(INOS)在创面表达，主要表达于巨噬细胞，在创面组织中表达。 修复前72小时。INOS的缺乏与伤口愈合受损有关。 《特殊目的II》将重点介绍iNOS衍生的NO在脑出血中的机制作用。 组织修复的过程。3)产生NO的细胞表现出代谢损伤 抑制底物氧化，增加糖酵解。在此期间工作 期间证明，一氧化氮诱导了一种新的酰基磷酸酶活性。 解偶联的糖酵解酶甘油醛-3-磷酸脱氢酶 来自三磷酸腺苷生产的糖酵解中的碳通量。《特定目标3》将继续 通过研究糖酵解能量产生的细节来研究这一领域的工作 炎性细胞。建议的研究完成后，应可进一步 对构成该过程的细胞和分子事件的理解 导致正常的组织修复。

DESCRIPTION (Verbatim from applicant's abstract) Wounds and their management remain the mainstay of surgical practice. Abnormal repair in diabetes, vascular disorders, malnutrition, infection and other clinical conditions challenge the practitioner and consume a substantial portion of health care dollars. The focal point of this project remains the study of the cellular and molecular biology of normal tissue repair, and is based on the premise that a full understanding of normal wound healing will provide essential footing to clinical intervention in abnormal repair. Specific Aims were designed by selecting among past fmdings those with the greatest potential to expand the mechanistic understanding of the regulation of inflammation and repair. Those observations and Specific Aims are: 1) Wound-derived macrophages actively induce apoptosis in wound polymorphonuclear leukocytes (PMN) through a specific effector mechanism comprising, at least, the expression of b3 integrins and membrane-bound TNF-a on the macrophage surface. Experiments proposed in Specific Aim I will expand on these paradigm-shifting observations by examining the role of TNF-a and its receptors in repair and by further defining the mechanisms of macrophage-dependent PMN apoptosis. 2) Inducible nitric oxide synthase (iNOS) is expressed in wounds mostly in macrophages and during the first 72 h of repair. Lack of iNOS is associated with impaired wound healing. Specific Aim II will focus on the mechanistic role of iNOS-derived NO in the process of tissue repair. 3) Cells producing NO exhibit metabolic injury with suppressed substrate oxidation and increased glycolysis. Work during this period demonstrated that NO induces a novel acyl phosphatase activity in the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase that uncouples carbon flux in glycolysis from ATP production. Specific Aim III will continue work in this area by investigating specifics of glycolytic energy production in inflammatory cells. Completion of the proposed studies should further the understanding of the cellular and molecular events that underlie the processes resulting in normal tissue repair.