Inductive Mechanisms and Roles of MMPs in Tendon Healing

MMP 在肌腱愈合中的诱导机制和作用

• 批准号: 7054039
• 负责人: TIMOTHY M RITTY
• 金额: $ 7.33万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054039
• 关键词: biological signal transduction; collagen; dogs; extracellular matrix; fibroblasts; gene expression profiling; integrins; laboratory mouse; metalloendopeptidases; regeneration; tendons; tissue /cell culture; wound healing

DESCRIPTION (provided by applicant): We have found that internal tendon cells live within a pericellular ECM that is between the cells and the load-bearing fibrillar type I collagen. Further, we have demonstrated that MMPs 2 and 9 are expressed in vivo after injury. Similarly, We have established that in vitro, tendon cells increase the production of MMP-2, MMP-9 and MMP-14 after attachment to type I collagen. Our overall hypothesis is: after injury, tendon cells proliferate and migrate and in so doing disrupt their previous steady-state ECM contacts and form new ECM interactions which include type I collagen. This change in ECM ligands, and our preliminary work suggests type I collagen ligation may be key, is part of the constellation of cues that result in the induction of wound healing proteins. As tendon healing then progresses, MMPs play an integral role in catabolic remodeling, growth factor modulation and new matrix deposition. To evaluate this general model of tendon healing, we propose the following in vivo and in vitro approaches: 1. expand our experimental manipulation of tendon cells in vitro to study the mechanisms by which ECM influences the expression of these genes. 2. examine in vivo the functional role of MMP-9 and MMP-14 in tendon repair by the evaluation of tendon healing in null mice. 3. carry out a survey of gene expression as a first step to understanding the greater context within which the collagen-elicited MMP response occurs.

描述(申请人提供)：我们发现肌腱内部细胞存在于细胞周围的细胞外基质中，该细胞介于细胞和承载纤维的I型胶原之间。此外，我们还证明了MMP2和MMP9在损伤后的体内表达。同样，我们已经证实，在体外，肌腱细胞在附着于I型胶原后，会增加基质金属蛋白酶-2、基质金属蛋白酶-9和基质金属蛋白酶-14的产生。我们的总体假设是：损伤后，肌腱细胞增殖和迁移，这样做破坏了它们先前稳定的ECM接触，形成了包括I型胶原在内的新的ECM相互作用。ECM配体的这种变化，以及我们的初步工作表明，I型胶原连接可能是关键，是导致诱导伤口愈合蛋白的一系列信号的一部分。随着肌腱愈合的进展，MMPs在分解代谢重塑、生长因子调节和新的基质沉积中发挥着不可或缺的作用。为了评估这一肌腱愈合的一般模型，我们提出了以下体内和体外的方法：1.扩大我们的体外肌腱细胞实验操作，以研究ECM影响这些基因表达的机制。2.通过对裸小鼠肌腱愈合的评价，在体内检测基质金属蛋白酶-9和基质金属蛋白酶-14在肌腱修复中的作用。3.进行基因表达调查，作为了解胶原蛋白诱导的基质金属蛋白酶反应发生的更大背景的第一步。