(OVERALL) This is a renewal application to continue the Brittle Bone Disorders Consortium of the Rare Diseases Clinical Research Network (BBDC RDCRN) for years 6-10. The BBDC is focused on rare bone diseases that are caused by defects in osteoblast differentiation and/or function which leads to qualitative and/or quantitative defects of bone, altered biomaterial properties such as mineralization, and/or downstream cellular changes in osteocytes and osteoclasts. These are represented by the different types of Osteogenesis Imperfecta (OI). While OI is often used interchangeably with BBD, the phenotypic spectrum is rapidly expanding. Moreover, there is a significant unmet need to understand the natural history of these phenotypes stratified by their molecular genetic etiologies. How these different mutations ultimately lead to brittle bone remains unknown and what are appropriate interventions and biomarkers of various disease morbidities are open questions. In years 1-5 of the BBDC, we met or exceeded accrual targets in 6 out of 7 protocols. We have published or have under review 12 manuscripts describing our cross sectional data. Importantly, our findings in the previous longitudinal study, pregnancy study, craniofacial study, pilot collagen crosslink biomarker study, and the PROMIS pilot study have empowered the design and inclusion of new elements in the current longitudinal study (Project 1), orthodontic clinical trial to treat malocclusion in OI (Project 2), and longitudinal biomarker study of growth (Project 3). This BBDC will be composed of 12 clinical sites covering the U.S. and Canada.
The Specific Aims of the BBDC are: i) To perform collaborative clinical research in brittle bone disorders including the three clinical projects listed above; ii) To train and attract a cohort of investigators in clinical bone research who will be recruited from undergraduate, post-baccalaureate, graduate, medical student, resident/fellow, and junior faculty ranks; and iii) to collaborate with the Osteogenesis Imperfecta Foundation (OIF) to expand a tool box of training materials that can be used to broadly educate patients, families, and healthcare provider across a broad spectrum of expertise.

Public Health Relevance

(OVERALL) This is a continuation years 6 to 10 in support of the Brittle Bone Disorders Consortium of the Rare Diseases Clinical Research Network (BBDC RDCRN). The goals are to work with our advocacy partner the Osteogenesis Imperfecta Foundation (OIF) to advance clinical trial readiness for the many types of Osteogenesis Imperfecta by performing a natural history study, a clinical trial of orthodontic intervention, and longitudinal biomarker study of growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54AR068069-06
Application #
9804535
Study Section
Special Emphasis Panel (ZTR1)
Program Officer
Chen, Faye H
Project Start
2014-08-06
Project End
2024-08-31
Budget Start
2019-09-13
Budget End
2020-08-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Dagdeviren, Didem; Tamimi, Faleh; Lee, Brendan et al. (2018) Dental and craniofacial characteristics caused by the p.Ser40Leu mutation in IFITM5. Am J Med Genet A :
Jain, Mahim; Tam, Allison; Shapiro, Jay R et al. (2018) Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study. Genet Med :
Najirad, Mohammadamin; Ma, Mang Shin; Rauch, Frank et al. (2018) Oral health-related quality of life in children and adolescents with osteogenesis imperfecta: cross-sectional study. Orphanet J Rare Dis 13:187
Tam, Allison; Chen, Shan; Schauer, Evan et al. (2018) A multicenter study to evaluate pulmonary function in osteogenesis imperfecta. Clin Genet 94:502-511
Lim, Joohyun; Grafe, Ingo; Alexander, Stefanie et al. (2017) Genetic causes and mechanisms of Osteogenesis Imperfecta. Bone 102:40-49
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
Grafe, Ingo; Alexander, Stefanie; Yang, Tao et al. (2016) Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta. J Bone Miner Res 31:1030-40
Bellur, S; Jain, M; Cuthbertson, D et al. (2016) Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. Genet Med 18:570-6
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