Low density lipoprotein receptor-related protein (LRP) is a multifunctional receptor which delivers its ligands to lysosomes and then rapidly recycles back to the cell surface. Although numerous LRP ligands have been identified, the function of this receptor remains unclear. Neutralization of LRP, in human and murine fibroblasts, promotes cellular adhesion, spreading, and motility selectively on vitronectin-coated surfaces. LRP neutralization also allows greatly increased accumulation of two related LRP ligands, urokinase-type plasminogen activator (u-PA) and the u-PA receptor (u-PAR), which have been strongly implicated in the regulation of adhesion and motility. The investigator hypothesizes that LRP neutralization alters the catabolism of u-PA and u-PAR so that the activity of the u-PA/u-PAR system is greatly increased and that this process is directly responsible for the observed changes in cellular adhesion and migration.
In Specific Aim 1, three subaims are proposed with the common goal of testing the major hypothesis. Human and murine fibroblast cell lines, in which LRP is neutralized, either at the level of expression or activity, will be studied in experiments designed to evaluate the u-PA/u-PAR system and cellular adhesion, spreading, and motility. Using these novel cell lines, the investigator will directly test whether the increase in activity of the u-PA/u-PAR system, which results from LRP neutralization, is responsible for the observed changes in cellular adhesion and migration. He will then elucidate the mechanism whereby LRP neutralization increases cell-surface expression of u-PAR and accumulation of u-PA in the medium.
Specific Aim 2 includes three subaims with the common goal of characterizing the potentially complex pathway through which LRP neutralization leads to the observed alterations in fibroblast adhesion and motility. The three subaims focus on the role of u-PAR-initiated signal transduction, the activities of vitronectin-binding integrins, and the contributions of plasminogen activator inhibitors. The studies proposed in this grant application will elucidate a defined activity of LRP, on a cell biological level, and contribute to our understanding of multiprotein systems involved in the regulation of cellular motility. The studies are relevant to diverse physiologic and pathophysiologic processes that require cellular adhesion and motility, including tumor invasion, the inflammatory response, angiogenesis, and atherosclerosis.
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