Laminins are integral basement membrane (BM) glycoproteins. Laminin-332 (Ln-332; formerly called laminin-5) comprised of laminin chains a3,, p.3 and y2 affects epithelial cell structure and function in many tissues. It is present in alveolar and airway subepithelial BMs, but its roles in lung injury and repair are unknown.
In Aim 1 we will study the turnover of lung Ln-332 under normal conditions and in settings of lung injury induced by Sendai virus, or exposures to cigarette smoke or napthalene. These studies will utilize a transgenic mouse that we have made that has a dox-inducible human laminin y2 transgene, that expresses human laminin y2, a laminin chain unique to Ln-332. The product of this transgene co-localizes with mouse Ln 332 in the lung and is incorporated into the mouse Ln-332 trimer. The presence and quantity of the human laminin y2 will be monitored immunohistochemically with an antibody that recognizes human laminin y2 but not mouse laminin y2, and by quantitative real time PCR.
In Aim 2 we will assess the role of Ln-332 in repair of alveolar and airway injury induced as in Aim 1. The rate and pattern of repair in response to injury will be determined in the context of over-expression of laminin y2 in the lung, induced by continuous administration of dox to human laminin y2 transgenic mice or in the absence of laminin y2 expression in the lung. While we have conventional y2 knockout mice, these can not be used directly for these studies as they survive only 2-5 days after birth as result of blistering and mucosal pathology that impairs suckling. However, we will rescue these knockout mice by driving the expression of human y2 under a keratinocytespecific promoter in the context of the laminin y2knockout background. Studies will also be done with lung epithelial cells isolated from laminin transgenic and Ln-332 deficient mice for analysis of functions such as migration, proliferation, and wound repair.
In Aim 3 we will assess how proteolytic, oxidative or nitrosative modifications of Ln 332 affect its activity in cell repair processes such as adhesion, proliferation and differentiation, and its susceptibility to proteolysis. Further, using ELISAs of cell supernatants and microarrays of inflammatory and structural cells exposed to fragmented or chemically modified Ln-332, we will extend our recent finding that Ln 332 fragments exhibit biological activity such as chemotactic activity for neutrophils. The studies proposed will contribute new information about lung BMs, an important structure in common lung disorders, such as the acute respiratory distress syndrome, pulmonary fibrosis, emphysema, and asthma.
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