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Abstract

Grant Number:	5R01AR036820-23
Project Title:	COLLAGEN GENE STRUCTURE AND EXPRESSION

PI Information:	Name	Email	Title
	OLSEN, BJORN R.	bolsen@hms.harvard.edu	HERSEY PROFESSOR OF CELL BIOLOGY

Abstract: DESCRIPTION (provided by applicant): 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.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
cell growth regulation, collagen, gene expression, histogenesis, protein structure function
age difference, angiogenesis, apoptosis, basement membrane, biological signal transduction, blood vessel disorder, eye circulation, eye disorder, gene mutation, intermolecular interaction, proteolysis, vascular endothelium
SDS polyacrylamide gel electrophoresis, antisense nucleic acid, electron microscopy, genetically modified animal, immunocytochemistry, laboratory mouse, terminal nick end labeling, tissue /cell culture

Institution:	HARVARD UNIVERSITY (MEDICAL SCHOOL)
	MEDICAL SCHOOL CAMPUS
	BOSTON, MA 02115
Fiscal Year:	2007
Department:	CELL BIOLOGY
Project Start:	01-JUL-1985
Project End:	30-JUN-2008
ICD:	NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG:	PBC

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