In close concert with projects 1 and 2, we seek common molecular features of abnormal bone collagen expression in tissue from mice and human cases of osteogenesis imperfecta (01) caused by mutations in genes encoding the CRTAP/P3H1/CYPB and FKBP10/HSP47 complexes and newly identified genes causing recessive 01. The significance and inter-relationships of defective prolyl 3-hydroxylation, associated post-translational over modification of lysine residues and abnormal cross-linking are the focus and basis of hypothesis-driven studies. One goal is to thoroughly test the possibility that abnormal post-translational chemistry, and in particular cross-linking, underlies the brittle bone phenotype. Though the focus is novel recessive forms of 01, the significance of the findings is likely to extend across all forms of 01.
The specific aims are directed at establishing the cross-linking phenotype of bone collagen from mouse models and available human 01 cases, seeking a common pathology and common underlying mechanism.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD070394-04
Application #
8696943
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
Hudson, David M; Archer, Marilyn; King, Karen B et al. (2018) Glycation of type I collagen selectively targets the same helical domain lysine sites as lysyl oxidase-mediated cross-linking. J Biol Chem 293:15620-15627
Alhamdi, Shatha; Lee, Yi-Chien; Chowdhury, Shimul et al. (2018) Heterozygous WNT1 variant causing a variable bone phenotype. Am J Med Genet A 176:2419-2424
Cundy, Tim; Dray, Michael; Delahunt, John et al. (2018) Mutations That Alter the Carboxy-Terminal-Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype. J Bone Miner Res 33:1260-1271
Cao, Felicia; Lu, Linchao; Abrams, Steven A et al. (2017) Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome. Hum Mol Genet 26:3046-3055
Maccarana, Marco; Svensson, René B; Knutsson, Anki et al. (2017) Asporin-deficient mice have tougher skin and altered skin glycosaminoglycan content and structure. PLoS One 12:e0184028
Hudson, D M; Garibov, M; Dixon, D R et al. (2017) Distinct post-translational features of type I collagen are conserved in mouse and human periodontal ligament. J Periodontal Res 52:1042-1049
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
Lietman, Caressa D; Lim, Joohyun; Grafe, Ingo et al. (2017) Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone. J Bone Miner Res 32:1354-1367
Zeng, Huan-Chang; Bae, Yangjin; Dawson, Brian C et al. (2017) MicroRNA miR-23a cluster promotes osteocyte differentiation by regulating TGF-? signalling in osteoblasts. Nat Commun 8:15000
Duran, Ivan; Martin, Jorge H; Weis, Mary Ann et al. (2017) A Chaperone Complex Formed by HSP47, FKBP65, and BiP Modulates Telopeptide Lysyl Hydroxylation of Type I Procollagen. J Bone Miner Res 32:1309-1319

Showing the most recent 10 out of 89 publications