The long-term goal of these studies is to understand the molecular basis for the assembly and the functions of specific tissues and organ structures. The work is focused on a component of the specialized extracellular matrices called basement membranes that underlie all epithelial and endothelial cells. The component, collagen XVIII, is the precursor of endostatin, a protein fragment shown to have antiangiogenic and antitumor activities in animal studies. One objective of the proposed work is to better understand the proteolytic processing events that lead to generation of endostatin and other collagen XVIII fragments and to determine whether such fragments have important physiological functions following their release from collagen XVIII. A second objective is to define the protein regions in collagen XVIII molecules that target the molecule to its location within basement membranes. A third objective is to understand why blood vessels present in the vitreous of the eye during development are not regressing as they normally do in the absence of collagen XVIII. A fourth goal is to understand the basis for the age-dependent accumulation of protein deposits behind the retina and the progressive reduction in retinal function in mice lacking collagen XVIII. To reach these goals we will use a combination of mouse genetics, cell biological and protein chemistry studies. Mutations in the gene for collagen XVIII in humans, resulting in the absence of both the collagen and the fragment endostatin, is the cause of Knobloch syndrome. Patients with this disorder have high myopia, vitreoretinal degeneration, retinal detachment, abnormal macular pigmentation, and loss of eyesight. We have generated a mouse model of Knobloch syndrome and plan a series of studies to determine both the mechanisms by which lack of collagen XVIII results in eye disease as well as the function of collagen XVIII/endostatin in regulation of angiogenesis and tumor growth.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Pathobiochemistry Study Section (PBC)
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Tyree, Bernadette
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Harvard University
Anatomy/Cell Biology
Schools of Medicine
United States
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