Proteoglycans, as components of extracellular matrices, participate in tissue morphogenesis and cell differentiation. On cell surfaces, they bind extracellular proteins, organize other cell surface molecules, and engage in endocytosis and cell adhesion. In-bred animals bearing mutations in proteoglycan assembly suffer from disproportionate dwarfisms. Numerous disorders in humans, including tumor formation correlate with aberrations in proteoglycan composition. The long range objective of this proposal is to analyze the relationship of proteoglycan structure, assembly and activity. These relationships will be studied in Chinese hamster ovary cells through mutations that block proteoglycan synthesis. Methods are described to study the glycosyltransferases responsible for assembly of the linkage tetrasaccharide common to chondroitin and heparan sulfate. These studies will establish if the individual biosynthetic pathways diverge during the assembly of the linkage region. Characterization of other mutants defective in the formation of chondroitin sulfate or heparan sulfate should reveal how the biosynthetic pathways are coordinated. Selection of mutations that augment the content of proteoglycans will identify rate-limiting enzymes and regulatory factors present in the system. Mutational studies permit the analysis of proteoglycan function without removing them from their normal cellular context. Studies of mutants lacking all proteoglycans demonstrated that these molecules are essential for endocytosis of thrombospondin and for cell attachment to defined extracellular matrices. These findings justify additional studies of mutants since other functions for proteoglycans may emerge. Dissection of the biosynthetic system by mutation should help define appropriate enzymatic targets for the development of metabolic inhibitors. This might lead to pharmacologic strategies for controlling the composition of proteoglycans in healthy and diseased tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM033063-04
Application #
3282423
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1983-07-01
Project End
1991-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
School of Medicine & Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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