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.
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