The accumulative, progressive remodeling of airways seen in many conditions, such as bronchiolitis obliterans, asthma, cystic fibrosis, and more, indicates that normal repair processes have gone awry. To understand the pathogenic mechanisms of destructive diseases, the mechanisms of normal airway repair need to be better understood. Injury sets off a programmed series of interdependent yet separate responses, such as re-epithelialization, inflammation, scarring, and eventually resolution. During each stage in this process, a number of extracellular proteinases are released by all cells. Acting on specific substrates, these enzymes serve numerous and diverse functions, including regulating cell-cell and cell-matrix signaling by both gain and loss-of-function mechanisms. In particular, members of the matrix metalloproteinase (MMP) family can activate the latent forms of a number of proteins involved in cellular communication, among several other functions. The goal of this project is to identify actual, physiologic protein substrates of specific MMPs, to understand the biological consequence of proteolytically processing a given protein, and to determine the regulation of MMP activity. Preliminary data with knock-out mice indicate that airway metalloproteinases, specifically, matrilysin (MMP7) and epilysin (MMP28), regulate distinct, non-overlapping processes essential for normal repair. Whereas matrilysin is required for re-epithelialization and neutrophil influx, epilysin seems to serve a more confined role to regulating generalized inflammation. The overall goals of this project are to determine the function of these MMPs in transplanted trachea and lung with and without underlying injury or infection.
For Aim 1, both in vivo and cell-based models will be used to assess the expression patterns, source, and function of matrilysin in airway repair and damage. The goal of these studies is to identify the substrate upon which matrilysin acts to facilitate re-epithelialization.
For Aim 2, the mechanisms regulating matrilysin's catalytic activity will be assessed, with a focus on the hypothesis that activation of the zymogen and inaction of the active enzyme are controlled by site-specific modifications mediated by neutrophil-generated oxidants, specifically HOCI.
For Aim 3, gene targeted mice will be used to test the idea that airway-derived epilysin regulates inflammation by proteolytic processing (i.e., activation) of a latent factor (e.g., a chemokine) or accessory protein (e.g., syndecans). These studies will demonstrate essential functions served by specific MMPs in airway repair. ? ? ?
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