The long-term goal of this proposal is to elucidate a novel genetic regulatory mechanism of skeletogenesis. For this purpose, we propose continued studies of a spontaneous mouse mutation, osteochondrodystrophy (Ocd). The Ocd mice is an autosomal recessive disorder associated with cartilage and bone defects. Our preliminary data demonstrate that the mutation in Ocd results in decreased chondrogenesis and bone formation during skeletal growth. The decreased chondrogenesis is due at least partially to increased expression of fibroblast growth factor receptor-3 (Fgfr-3) in cartilage growth plates. The finding form the basis of our hypothesis that Ocd is a regulator of chondrogenesis and osteogenesis and an alteration in Ocd, such as point mutation and deletion causes the skeletal abnormality during development. To test our hypothesis, we propose the following Specific Aims: 1) To identify ocd. On the basis of our high-resolution genetic linkage and physical maps of the Ocd locus, we have positioned Ocd in a chromosome region including1.1 million base-pairs containing 31 genes. To identify Ocd, we plan to examine the coding regions of these genes by direct DNA sequence analysis. 2) To examine the expression profile of Ocd and its down-stream effects on chondrogenesis. Once Ocd is identified, we plan to examine the expression pattern of Ocd by mRNA in situ hybridization and immunohistochemistry. To study the effect of the Ocd mutation on skeletogenesis, we first focus on the effect of the Ocd mutation on chondrogenesis. We will confirm our observation that the protein expression of Fgfr-3 is elevated in cartilage growth plates by examining mRNAs isolated from defined microdissected growth plate regions. We will also examine mRNA levels of Star-5 and p18 that are considered the down-stream targets of Fgfr-3. This study should provide novel insights into genetic regulation of skeletogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR050001-02
Application #
6738963
Study Section
Special Emphasis Panel (ZAR1-RJB-A (J1))
Program Officer
Sharrock, William J
Project Start
2003-04-22
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$84,375
Indirect Cost
Name
Harvard University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115