EXTRACELLULAR MATRIX BIOLOGY OF FIBULIN-1

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Fibulin-1 is a novel extracellular matrix (ECM) and blood protein recently found to be a component of connective tissue elastic fibers which are abundant in tissues such as skin, lung and blood vessels. The objectives of experiments proposed in this application are to determine the function of fibulin-1 in its context as an EcM and blood protein. The first specific aim is to identify the molecular interactions that account for its association with connective tissue elastic fibers and to determine whether fibulin-1 plays a role in the process of fibrogenesis. In addition, experiments will be performed to determine whether any of the many connective tissue diseases that involve elastic fibers are caused by abnormalities in fibulin-1 expression or function. The second aim of this application seeks to determine whether fibulin-1 has a role in the process of hemostasis since it promotes platelet adhesion and spreading, is a component of the vascular subendothelial matrix, and binds to fibrinogen. Studies will be done to gain an understanding of the role of fibulin-1 in the primary adhesion events that lead to platelet binding to subendothelial ECM, to identify the platelet surface molecule(s) that mediates interaction with fibulin-1 and to determine if fibulin-1 contributes to fibrin clot formation and stabilization through its interaction with fibrin. In the proposed research, an emphasis is placed on determining the function of fibulin-1 in the context of the vasculature however, the findings are expected to have broader implications given the widespread expression of this novel protein,in other connective tissues.