The Role of TIMP-1 in Airway Epithelial Repair

TIMP-1 在气道上皮修复中的作用

• 批准号: 7790603
• 负责人: PETER CHEN
• 金额: $ 12.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790603
• 关键词: Affinity; Allogenic; Allografting; Attenuated; Award; Binding; Bleomycin; Bronchiolitis; Bronchoalveolar Lavage Fluid; Cells; Cessation of life; Chronic; Critical Care; Development; Disease; Disease Progression; Doctor of Medicine; Doctor of Philosophy; E-Cadherin; Educational Curriculum; Epithelial; Epithelial Cells; Epithelium; Fibrosis; Goals; Graft Rejection; Hamman-Rich syndrome; Healed; Hematopoietic; In Vitro; Inflammation; Injury; Isogenic transplantation; Link; Lung; Lung diseases; Matrilysin; Matrix Metalloproteinases; Mediating; Medicine; Modeling; Mus; Naphthalene; Naphthalenes; Pathogenesis; Peptide Hydrolases; Play; Proteolysis; Research; Research Personnel; Respiratory Failure; Role; Source; System; Testing; Therapeutic; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinases; Trachea; Transplant Recipients; Transplantation; Wound Healing; abstracting; airway epithelium; base; career; cell motility; healing; in vitro activity; in vivo; injured; insight; migration; mortality; novel; overexpression; programs; repaired; restraint; therapy development; transplantation typing

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)

描述（由申请人提供）： 该提议的职业目标是成为肺和重症监护医学领域的独立研究者。该奖项描述了一项集成的课程，将教学课程与M.D. David Madtes赞助的研究计划相结合，该计划是金属蛋白酶（TIMPS）的组织抑制剂领域的专家，并由William Parks，Ph.D。共同赞助，这是Matrix Metallopoteinass（MMPS）的专家。闭塞性支气管炎（OB）是慢性肺移植排斥的病理标志，具有高死亡率和无效的治疗方法。 OB的发病机理在很大程度上尚不清楚，但研究表明，疾病的发展与气道上皮的破坏有关。母脂蛋白（MMP-7）对于气道上皮修复是必需的，其体外蛋白水解活性受到TIMP-1的抑制。因此，可以合理地推测TIMP-1通过沉默MMP-7活性在上皮修复中起着调节作用。在OB的鼠模型中，我们发现TIMP-1表达在 同种异体气管！移植物，并在上皮期间位于A I对数筏上皮 维修。此外，并支持TIMP-1有助于疾病进展的想法 使用TIMP-1缺乏供体或接受者的气管减少了腔室闭塞，更完整 与移植到野生型接受者的上皮修复相比。相比之下，与野生型等渗移植物不同，母氏蛋白质缺陷小鼠的同射手移植显示出持续的上皮损伤和粘膜下炎。因此，我的中心假设是TIMP-1减弱了体内母氏活性，并且这种抑制作用会干扰母脂依赖的气道上皮修复。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中的细胞贡献。在特定的目标2中，我将研究TIMP-1限制使用体外和离体培养系统的气道上皮修复的机制。在特定的目标中，3,1将证明TIMP-1与母氏菌蛋白结合并破坏体内天生蛋白的活性以抑制气道上皮修复。这些研究将提供有关TIMP-1调节气道上皮修复的基本机制的洞察力，其在诸如OB之类的疾病中的潜在治疗意义。 （抽象的结尾）