The Role of TIMP-1 in Airway Epithelial Repair

描述（由申请人提供）： 该提案的职业目标是成为肺和重症监护医学领域的独立调查员。该奖项描述了一个综合课程结合教学课程与研究计划赞助的大卫马特斯，医学博士，金属蛋白酶组织抑制剂（TIMPs）领域的专家，由William Parks博士共同赞助，他是基质金属蛋白酶（MMPs）领域的专家。闭塞性细支气管炎（obliterative bronchiolitis，OB）是肺移植慢性排斥反应的病理标志，病死率高，治疗无效。OB的发病机制在很大程度上是未知的，但研究表明，疾病的发展与气道上皮细胞的破坏有关。基质溶素（MMP-7）是气道上皮修复所必需的，其体外蛋白水解活性可被TIMP-1抑制。因此，推测TIMP-1通过沉默MMP-7活性在上皮修复中起调节作用是合理的。在OB小鼠模型中，我们发现TIMP-1表达在OB小鼠中增加。 同种异体气管!移植，并在上皮移植期间定位于a1 log筏上皮。 修复.此外，支持TIMP-1促进疾病进展的观点，同种异体移植物 使用TIMP-1缺陷供体或受体的气管管腔闭塞减少， 与移植到野生型受体中的那些相比，上皮修复。相反，与野生型同种异体移植物不同，基质溶解素缺陷小鼠的同种异体移植物表现出持续的上皮损伤和粘膜下炎症。因此，我的中心假设是TIMP-1在体内减弱基质溶解素活性，这种抑制干扰基质溶解素依赖性气道上皮修复。在特定目的1中，1将确定TIMP-1在异位气管移植模型中气道闭塞发展中的细胞作用。在具体目标2中，我将使用体外和离体培养系统研究TIMP-1限制基质溶解素介导的气道上皮修复的机制。在具体目标3中，1将证明TIMP-1与基质溶解素结合并破坏体内基质溶解素活性以抑制气道上皮修复。这些研究将提供对TIMP-1调节气道上皮修复的基本机制的深入了解，对OB等疾病具有潜在的治疗意义。 (End摘要）

DESCRIPTION (provided by applicant): The career goal of this proposal is to become an independent investigator in the field of Pulmonary and Critical Care Medicine. This award describes an integrated curriculum combining didactic coursework with a research program sponsored by David Madtes, M.D., an expert in the field of tissue inhibitors of metalloproteinases (TIMPs), and co-sponsored by William Parks, Ph.D., an expert in the field of matrix metalloproteinases (MMPs). Obliterative bronchiolitis (OB) is the pathological hallmark of chronic lung transplant rejection with high mortality and ineffective treatments. The pathogenesis of OB is largely unknown, but studies show that disease development is linked to destruction of the airway epithelium. Matrilysin (MMP-7) is necessary for airway epithelial repair, and its proteolytic activity in vitro is inhibited by TIMP-1. Therefore, it is reasonable to speculate that TIMP-1 serves a regulatory role in epithelial repair by silencing MMP-7 activity. In a murine model of OB, we have found that TIMP-1 expression is increased in allogeneic trachea! transplants and is localized to the a I log raft epithelium during the period of epithelial repair. Furthermore, and supporting the idea that TIMP-1 contributes to disease progression, allogeneic tracheas using TIMP-1 deficient donors or recipients had decreased luminal obliteration and more complete epithelial repair compared to those transplanted into wild-type recipients. In contrast, isografts from matrilysin deficient mice showed sustained epithelial damage and submucosal inflammation unlike wild-type isografts. Therefore, my central hypothesis is that TIMP-1 attenuates matrilysin activity in vivo, and this inhibition interferes with matrilysin-dependent airway epithelial repair. In Specific Aim 1,1 will determine the cellular contribution of TIMP-1 in the development of airway obliteration in the heterotopic tracheal transplant model. In Specific Aim 2, I will investigate the mechanisms by which TIMP-1 limits matrilysin-mediated airway epithelial repair using in vitro and ex vivo culture systems. In Specific Aim 3,1 will demonstrate that TIMP-1 binds to matrilysin and disrupts matrilysin activity in vivo to inhibit airway epithelial repair. These studies will provide insight into the basic mechanisms by which TIMP-1 regulates airway epithelial repair with potential therapeutic implications in diseases such as OB. (End of Abstract)