The Role of TIMP-1 in Airway Epithelial Repair

描述(由申请人提供)： 这项提案的职业目标是成为肺部和重症监护医学领域的独立研究员。该奖项描述了将教学课程与研究计划相结合的综合课程，该课程由金属蛋白酶组织抑制物(TIMPs)领域的专家David Madtes医学博士发起，并由基质金属蛋白酶(MMPs)领域的专家William Parks博士共同赞助。闭塞性毛细支气管炎(OB)是慢性肺移植排斥反应的病理特征，死亡率高，治疗效果差。OB的发病机制在很大程度上尚不清楚，但研究表明，疾病的发展与呼吸道上皮的破坏有关。基质分解素(MMP7)是呼吸道上皮修复所必需的，其体外蛋白分解活性可被TIMP-1抑制。因此，有理由推测TIMP-1通过抑制基质金属蛋白酶-7的活性在上皮修复中发挥调节作用。在OB小鼠模型中，我们发现TIMP-1在 同种异体气管！移植物，并在上皮时期定位于移植物上皮 修理。此外，支持TIMP-1有助于疾病进展的观点，异基因 使用TIMP-1缺乏的供体或受体的气管减少了管腔闭塞，并且更完整 与移植到野生型受体中的上皮修复相比。相反，与野生型同种异体移植物不同，来自母溶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在体内减弱了基质溶素的活性，这种抑制作用干扰了基质溶素依赖的呼吸道上皮修复。在特定的目标中，1，1将确定TIMP-1在异位气管移植模型中气道闭塞发展过程中的细胞作用。在具体目标2中，我将利用体外和体外培养系统研究TIMP-1限制基质溶素介导的呼吸道上皮修复的机制。在特定的目标3，1中，将证明TIMP-1与基质溶素结合，并在体内破坏基质溶素的活性，以抑制呼吸道上皮修复。这些研究将深入了解TIMP-1调节呼吸道上皮修复的基本机制，对OB等疾病具有潜在的治疗意义。 (摘要结束)

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)