Proteoglycans are essential extracellular components for normal development and maintenance of cartilage tissue. This has been most convincingly demonstrated by studies on certain mutant model systems which exhibit altered cartilage development and/or organization resulting in abnormal growth patterns. In two particular model systems, which we have examined, defects have been localized exclusively to the pathway of proteoglycan synthesis. Although the defects have been conclusively identified in these two cases, the relationship between abnormal proteoglycan production and aberrant growth cannot yet be described. It is therefore our objective, through a multi-faceted approach, to use these animal model systems, 1) to correlate the biochemical defect with abnormal biological function, 2) to study the regulation of gene expression during cartilage differentiation in the abnormal situations, 3) to attempt to ameliorate the biological effect of the defect in the mutant animals and 4) to extend these animal studies to the heterogeneous group of human disorders, the skeletal dysplasias, some of which may have associated proteoglycan deficiencies. To accomplish this objective, a comprehensive research plan to characterize the defective protein molecules that have been identified in these two mutant systems, at the molecular and genetic level is described. Methodology to be employed includes all of the biochemical, immunological, histological, and molecular approaches is current use for the preceeding studies of this proposal and for other projects in our program. A new approach to be developed during the future proposal is the generation of long-term chondrocyte cell lines from normal and mutant animal and human sources. These cell lines should prove valuable for our proposed studies and for others interested in cartilage differentiation and disorders. All of these studies should aid ultimately in the elucidation of certain human skeletal dysplasias about which virtually nothing is known at the molecular level, and open up a range of possibilities for studies on hormone or gene replacement therapy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD017332-04A2
Application #
3314306
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1983-04-01
Project End
1992-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Cortes, Mauricio; Cortes, Leslie K; Schwartz, Nancy B (2015) Mapping proteoglycan functions with glycosidases. Methods Mol Biol 1229:443-55
Lauing, Kristen L; Cortes, Mauricio; Domowicz, Miriam S et al. (2014) Aggrecan is required for growth plate cytoarchitecture and differentiation. Dev Biol 396:224-36
Schwartz, Nancy B; Domowicz, Miriam S (2014) Chemistry and function of glycosaminoglycans in the nervous system. Adv Neurobiol 9:89-115
Mis, Emily K; Liem Jr, Karel F; Kong, Yong et al. (2014) Forward genetics defines Xylt1 as a key, conserved regulator of early chondrocyte maturation and skeletal length. Dev Biol 385:67-82
Bradley, Michael E; Rest, Joshua S; Li, Wen-Hsiung et al. (2009) Sulfate activation enzymes: phylogeny and association with pyrophosphatase. J Mol Evol 68:1-13
Domowicz, Miriam S; Cortes, Mauricio; Henry, Judith G et al. (2009) Aggrecan modulation of growth plate morphogenesis. Dev Biol 329:242-57
Pirok 3rd, Edward W; Domowicz, Miriam S; Henry, Judith et al. (2005) APBP-1, a DNA/RNA-binding protein, interacts with the chick aggrecan regulatory region. J Biol Chem 280:35606-16
Singh, Bhawani; Schwartz, Nancy B (2003) Identification and functional characterization of the novel BM-motif in the murine phosphoadenosine phosphosulfate (PAPS) synthetase. J Biol Chem 278:71-5
Kurima, K; Singh, B; Schwartz, N B (1999) Genomic organization of the mouse and human genes encoding the ATP sulfurylase/adenosine 5'-phosphosulfate kinase isoform SK2. J Biol Chem 274:33306-12
Deyrup, A T; Krishnan, S; Singh, B et al. (1999) Activity and stability of recombinant bifunctional rearranged and monofunctional domains of ATP-sulfurylase and adenosine 5'-phosphosulfate kinase. J Biol Chem 274:10751-7

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