Osteoarthritis is a chronic debilitating disease that affects up to 1/3 of the adult population. Growing evidence suggests that genetic factors influence its development, and a better understanding of inherited chondrodysplasias will undoubtedly shed light on the processes common to all degenerative joint disease. Spondyloepiphyseal dysplasia tarda (SEDL) is a chondrodysplasia that is characterized by disproportionate short stature, X-linked inheritance, and early-onset osteoarthritis. We have recently identified the gene responsible for this disorder, and have characterized numerous mutations responsible for the SEDL phenotype--However, the function of the SEDL gene product, """"""""sedlin,"""""""" remains to be elucidated. In order to determine the role played by the sedlin protein in maintaining cartilage integrity, the following goals are proposed: 1) to determine the biochemical structure and properties of sedlin, 2) to determine the subcellular localization of sedlin and its expression pattern throughout murine chondrogenesis, 3) to determine the proteins with which sedlin associates, 4) to establish an animal model for SEDL, and 5) to test the genes of proteins associated with sedlin as candidate osteciarthritis susceptibility genes. To fulfill these aims, we propose to 1) express native sedlin in vitro and study its structure by NMR spectroscopy and X-ray crystallography, 2) determine its subcellular localization using subcellular fractionation, Western blotting, and immunoelectron microscopy; follow its expression during murine chondrogenesis, 3) identify sedlin-associated proteins by immunoprecipitation and find polymorphisms in their genes, 4) create knockout mice for the SEDL locus and examine their histologic phenotype from embryo through senescence, and 5) test the genes identified in (3) as candidate genes for osteoarthritis susceptibility within a case-control cohort with idiopathic osteoarthritis. Elucidation of the expression pattern and function of the SEDL gene may provide clues for designing therapeutic modalities for individuals affected with SEDL. Moreover, we anticipate that these studies will yield valuable insight into the role of the sedlin pathway in maintaining cartilage integrity and its derangement in osteoarthritis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049529-04
Application #
6950447
Study Section
Special Emphasis Panel (ZAR1-TAS-B (O2))
Program Officer
Tyree, Bernadette
Project Start
2002-09-20
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2005
Total Cost
$309,550
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212