COLLAGEN METABOLISM IN WOUND REPAIR

描述（来自申请人摘要的逐字逐句）压疮是 老年人和脊髓所面临的最衰弱和最昂贵的问题 受伤的病人。对这一日益严重的问题的处理仍然是经验主义的。进展 在开发用于改善压疮治疗的策略方面， 由于缺乏对压力的基本定义， 溃疡微环境和潜在的细胞、生化和分子 导致这些病变愈合率差的机制。 因此，我们一直在研究这一假设，并获得了大量证据， 这些病变的慢性化与蛋白水解增强有关， 与多形核菌过度存在相关的环境 白细胞（中性粒细胞）。中性粒细胞是体内主要的炎症细胞 压力性溃疡，并且是许多蛋白酶的来源，包括 胶原酶（MMP-8）和弹性蛋白酶。最近的调查结果基于现场 杂交分析表明，压力床中的间充质细胞 溃疡中含有丰富的前胶原转录物，这表明 细胞具有合成活性。因此，本项目的主要目标 将是测试假设，即过度的蛋白水解环境可以 而这一点，也将随着时间的推移而逐渐消失。 胶原蛋白基质的积累，恢复生长的完整性的关键 因子受体此外，假设合成/降解 压力性溃疡的平衡可以使用治疗剂改变 也将测试批准用于人类的药物。纵向表征 包括中性粒细胞的组织化学鉴定， 其他细胞群，蛋白酶水平和活性的评估 主要是嗜水气单胞菌衍生的， 蛋白酶抑制剂细胞外基质的表达将通过 分析胶原蛋白的合成和沉积， 原胶原转录物。类似地，生长因子受体的表达将 通过定性和定量蛋白质评估以及原位 杂交和定量核糖核酸酶保护测定。这些数据应 为制定新战略提供关键信息， 治疗压疮以及其他慢性不愈合伤口。

DESCRIPTION (Verbatim from the applicant's abstract) Pressure ulcers are one of the most debilitating and costly problems faced by elderly and spinal cord injury patients. Treatment of this growing problem remains empirical. Progress in the development of strategies for improving treatment of pressure ulcers has been hampered greatly by the lack of a fundamental definition of the pressure ulcer microenvironment and the underlying cellular, biochemical, and molecular mechanisms responsible for the poor rate of healing of these lesions. Therefore we have pursued the hypothesis and generated extensive evidence that the chronicity of these lesions is related to the enhanced proteolytic environment associated with an over exuberant presence of polymorphonuclear leukocytes (neutrophils). Neutrophils are the predominant inflammatory cell in pressure ulcers and are a source for a number of proteinases including collagenase (MMP-8) and elastase. Recent findings based on in situ hybridization analyses, indicate that mesenchymal cells in the beds of pressure ulcers contain abundant levels of procollagen transcripts suggesting that these cells are synthetically active. Therefore, the major objective of this project will be to test the hypothesis that the excessive proteolytic environment can be diminished by good wound care and this will be associated with increased collagen matrix accumulation, and restitution of the integrity of key growth factor receptors. In addition, the hypothesis that the synthetic/degradative equilibrium of pressure ulcers can be altered using a therapeutic agent already approved for use in humans will also be tested. A longitudinal characterization of pressure ulcers will include histochemical identification of neutrophils and other cell populations, an assessment of levels and activities of proteinases that are primarily neutrophil-derived, and measurement of levels of specific proteinase inhibitors. Expression of extracellular matrix will be monitored by analyzing collagen synthesis and deposition and the location and levels of procollagen transcripts. Similarly, expression of growth factor receptors will be examined by qualitative and quantitative protein assessment and by in situ hybridization and quantitative ribonuclease protection assay. These data should provide key inforrnation for the development of new strategies for the treatment of pressure ulcers as well as other chronic non-healing wounds.