The long-term goal of this application is to understand the biological function of Fibulin-2, a recently identified extracellular matrix protein. Fibulin-2 belongs to a growing super-family of extracellular matrix proteins that contain tandem arrays of calcium-binding EGF-like repeats. It is found both in the basement membranes, and interstitial connective tissues of many organs, including the heart, skin, skeletal muscle, cornea, kidney and blood vessels. In vitro binding assays show that fibulin-2 interacts with fibronectin, nidogen/entactin, fibrillin-1, and several other extracellular matrix ligands. In addition, fibulin-2 colocalizes with fibrillin-1 in microfibrils of some tissues. These observations suggest that fibulin-2 can be incorporated into different types of extracellular matrices and may play critical roles in diverse biological processes. In order to elucidate the biological function of fibulin-2, the following Specific Aims are proposed: (1) to study the biosynthesis, processing and assembly of fibulin-2 in cultured cells; (2) to study the structure/function of fibulin-2, by using recombinant fibulin-2 fragments to identify domains responsible for binding fibronectin, nidogen, fibrillin-1, and for matrix assembly; (3) to prepare transgenic mice with the fibulin-2 gene inactivated, or mutated, in order to investigate the consequences of the mutations; and (4) to characterize the promoter region of the mouse fibulin-2 gene and identify elements controlling the gene expression.
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