Abstract

The skeletal dysplasias are a heterogeneous group of disorders which result in disproportionate short stature and/or skeletal deformities. Although they have long been considered to be generalized disorders of endochondral and/or membraneous ossification, the extent of their heterogeneity has only recently been recognized and little is known concerning their pathogenesis. This project is directed toward a multidisciplinary investigation of the clinical, genetic, morphological and biochemical characteristics of the skeletal dysplasias.
The specific aims of this proposal will be: a) definition of the clinical, radiographic and genetic heterogeneity of the skeletal dysplasias; b) definition of the natural history, growth characteristics and complications of each of these disorders; c) delineation of the dynamics of craniofacial growth and development in each of these disorders; d) elucidation of the histological, histochemical, and ultrastructural characteristics of chondro-osseous tissue in each of these diseases; e) detailed analysis of the collagen composition of normal human fetal and postnatal cartilage; f) elucidation of the basic biochemical defects in each of these diseases by means of biochemical analysis of cartilage and metabolic studies of cultured chondrocytes; g) identification and investigation of specific animal models of the human chondrodystrophies; h) establishment of an International Registry of Dysplastic Skeletal Tissues. This program is divided into three separate grant proposals: 1) Clinical and Morphological studies, which will attempt to delineate the clinical and radiographic characteristics of these disorders, study the morphology and ultrastructure of their chondro-osseous tissue and identify and investigate specific animal models of these human disorders; 2) Collagen Polymorphism of Human Cartilage which will attempt to characterize the new varieties of collagen found in human cartilage and investigate their distribution and age related changes; and 3) Biochemical Studies of the Chondrodystrophies, which will attempt to define the molecular defects of chondrodystrophic cartilage components and characterize each of these aberrations.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD022657-04
Application #
3097086
Study Section
Maternal and Child Health Research Committee (HDMC)
Project Start
1986-12-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048

  Publications

Joeng, Kyu Sang; Lee, Yi-Chien; Lim, Joohyun et al. (2017) Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. J Clin Invest 127:2678-2688
Madan, Simran; Liu, Wei; Lu, James T et al. (2017) A non-mosaic PORCN mutation in a male with severe congenital anomalies overlapping focal dermal hypoplasia. Mol Genet Metab Rep 12:57-61
Rajagopal, Abbhirami; Homan, Erica P; Joeng, Kyu Sang et al. (2016) Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice. Mol Genet Metab 117:378-82
Xue, Yuan; Schoser, Benedikt; Rao, Aliz R et al. (2016) Exome Sequencing Identified a Splice Site Mutation in FHL1 that Causes Uruguay Syndrome, an X-Linked Disorder With Skeletal Muscle Hypertrophy and Premature Cardiac Death. Circ Cardiovasc Genet 9:130-5
Lietman, Caressa D; Marom, Ronit; Munivez, Elda et al. (2015) A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation. J Bone Miner Res 30:489-98
Hudson, David M; Joeng, Kyu Sang; Werther, Rachel et al. (2015) Post-translationally abnormal collagens of prolyl 3-hydroxylase-2 null mice offer a pathobiological mechanism for the high myopia linked to human LEPREL1 mutations. J Biol Chem 290:8613-22
Chen, Shan; Grover, Monica; Sibai, Tarek et al. (2015) Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton. Mol Genet Metab 115:53-60
Weinstein, Michael M; Tompson, Stuart W; Chen, Yuqing et al. (2014) Mice expressing mutant Trpv4 recapitulate the human TRPV4 disorders. J Bone Miner Res 29:1815-1822
Joeng, Kyu Sang; Lee, Yi-Chien; Jiang, Ming-Ming et al. (2014) The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations. Hum Mol Genet 23:4035-42
Campeau, Philippe M; Kasperaviciute, Dalia; Lu, James T et al. (2014) The genetic basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol 13:44-58

Showing the most recent 10 out of 365 publications