MECHANISMS OF FETAL WOUND REPAIR--CELLULAR AND MOLECULAR

这个项目的长期目标是扩大视野和 促进人类胎儿手术后的愈合以及更好的发展 成人创面愈合的临床处理 有问题。胎儿的伤口通过显著的 不同于那些参与成人治疗的人。没有一位 急性炎症、纤维化和收缩，其结果很少或没有 疤痕形成。这种治愈既是表面上的，也是功能上的 优于成人修复，胎儿伤口可恢复到正常的60% 受伤后两周内的皮肤破裂力，而在成年人中 需要几个月的时间，只达到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)，这项建议侧重于 胎儿和成人成纤维细胞的细胞外基质代谢。少校 这一提议的重点是检验胶原和HA表达的假设 它们在胎儿成纤维细胞中的调控与 成体成纤维细胞。初步研究将确定 成人和胎儿成纤维细胞的胶原和胶原酶的体外研究 和活体内(主要是闭合伤口和开放伤口)。这 表征将包括形态和生化分析 由正常胎儿和成人成纤维细胞组成的四种不同类型的细胞 以及胎儿和成人伤口成纤维细胞。要确定机制， 在矩阵的微分表达的基础上，这一分析将是 延伸到分子水平。胶原蛋白、胶原酶、透明质酸和细胞因子 将考察文字记录的合成和积累。一旦这些 基线参数被确定，这些细胞对 调节细胞增殖和基质代谢的介质将是 测试过。此外，负责不收缩的机制 将对胎儿开放性伤口进行检查。 这项研究产生的信息将提供更好的理解 胎儿生理和发育。了解生物的基本生物学知识 胎儿修复过程应提高子宫手术的成功率 对出生异常的干预。此外，这种理解将导致 为更好地治疗人类伤口愈合提供更好的临床依据 瘢痕疙瘩、增生性烧伤疤痕和肌挛缩症等问题 作为慢性不可愈合的伤口，如压疮，糖尿病溃疡， 静脉淤积性溃疡是一个日益严重的卫生保健问题，并导致 主要的发病率和成本。治疗这些病理过程的新方法 可能是基于胎儿愈合的知识开发的，这可能导致 与此相关的发病率、死亡率和费用显著降低 这些问题。

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.