MECHANISMS OF FETAL WOUND REPAIR--CELLULAR AND MOLECULAR

胎儿伤口修复机制——细胞和分子

• 批准号: 2185038
• 负责人: ROBERT F DIEGELMANN
• 金额: $ 33.6万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2185038
• 关键词: SDS polyacrylamide gel electrophoresis; aging; cell cycle; cell type; collagen; collagenase; contracture; cytokine; embryo /fetus surgery; embryo /fetus tissue /cell culture; extracellular matrix proteins; fibroblasts; gene expression; genetic transcription; hyaluronate; in situ hybridization; interleukin 1; laboratory rabbit; mature animal; messenger RNA; mixed tissue /cell culture; platelet derived growth factor; protein metabolism; proteolysis; transforming growth factors; wound healing

The long-term objective of this project is to expand the horizons and improve the healing after fetal surgery in humans as well as develop better clinical treatments for the management of adult human wound healing problems. Wounds in the fetus heal by mechanisms which are significantly different than those involved in adult healing. There is an absence of acute inflammation, fibrosis, and contraction with resultant minimal or no scar formation. This healing is both cosmetically and functionally superior to adult repair in that fetal wounds regain up to 60% of normal skin breaking strength within two weeks of injury, whereas, in adults this takes many months and only gets to 40% (See page 20 of this application.) Because scarring is a result of synthesis, deposition, and degradation of collagen and hyaluronate (HA), this proposal focuses on the differences in extracellular matrix metabolism by fetal and adult fibroblasts. The major focus of this proposal tests the hypothesis that collagen and HA expression and their regulation in fetal fibroblasts is fundamentally different from adult fibroblasts. Initial studies will characterize the expression of collagen and collagenolytic enzymes by adult and fetal fibroblasts in vitro and in vivo (primarily closed wounds, and open wounds). This characterization will involve morphological and biochemical analyses of four different cell types consisting of normal fetal and adult fibroblasts as well as fetal and adult wound fibroblasts. To determine the mechanisms underlying the differential expression of matrix this analysis will be extended to the molecular level. Collagen, collagenase, HA, and cytokine transcript synthesis and accumulation will be examined. Once these baseline parameters are determined, the response of these cells to mediators which regulate cell proliferation and matrix metabolism will be tested. In addition, the mechanisms responsible for non-contraction of open fetal wounds will be examined. Information generated by this study will provide a better understanding of fetal physiology and development. Understanding the basic biology of the fetal repair process should improve successful in utero surgical intervention of birth anomalies. In addition, this understanding will lead to better clinical rationales for treating the many human wound healing problems such as keloid, hypertrophic burn scar, and contractures as well as chronic non-healing wounds such as pressure sores, diabetic ulcers, venous stasis ulcers that are a growing health care problem and result in major morbidity and costs. New treatments for these pathologic processes may be developed based on knowledge of fetal healing which could result in a marked reduction in the morbidity, mortality, and expense associated with these problems.

该项目的长期目标是扩大视野和 改善人类胎儿手术后的愈合以及更好地发育 管理成人伤口愈合的临床治疗 问题。 胎儿的伤口通过显着的机制愈合 与成人治疗所涉及的不同。 缺少 急性炎症、纤维化和收缩，产生的影响很小或没有 疤痕形成。 这种治愈既具有美观性又具有功能性 优于成人修复，胎儿伤口可恢复至正常状态的 60% 受伤后两周内的皮肤断裂强度，而对于成年人来说， 需要几个月的时间，但只能达到 40%（请参阅本申请的第 20 页。） 因为疤痕是合成、沉积和降解的结果 胶原蛋白和透明质酸（HA），该提案重点关注两者之间的差异 胎儿和成人成纤维细胞的细胞外基质代谢。 主要 该提案的重点测试了胶原蛋白和 HA 表达的假设 它们在胎儿成纤维细胞中的调节与 成体成纤维细胞。 初步研究将表征 成人和胎儿成纤维细胞体外产生的胶原蛋白和胶原蛋白分解酶 和体内（主要是闭合伤口和开放伤口）。 这 表征将涉及形态学和生化分析 由正常胎儿和成人成纤维细胞组成的四种不同细胞类型 以及胎儿和成人伤口成纤维细胞。 确定机制 该分析的基础是矩阵的差异表达 扩展到分子水平。 胶原蛋白、胶原酶、HA ​​和细胞因子 将检查转录本的合成和积累。 一旦这些 确定基线参数后，这些细胞对 调节细胞增殖和基质代谢的介质 已测试。 此外，负责不收缩的机制 将检查胎儿开放性伤口。 这项研究产生的信息将有助于更好地理解 胎儿生理和发育。 了解基本生物学 胎儿修复过程应提高子宫手术的成功率 出生异常的干预。 此外，这种理解将导致 为治疗许多人类伤口愈合提供更好的临床原理 疤痕疙瘩、肥厚性烧伤疤痕和挛缩等问题 慢性不愈合伤口，如压疮、糖尿病溃疡、 静脉淤滞性溃疡是一个日益严重的医疗保健问题，并导致 主要发病率和费用。 这些病理过程的新疗法 可能是基于胎儿愈合的知识而开发的，这可能会导致 发病率、死亡率和相关费用显着降低 这些问题。