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RESEARCH INTERESTS:
Genetic Regulation of Bone Formation: Genetic diseases of bone formation and development. Molecular and cell biology of bone formation and osteoblast differentiation. Cell signaling pathways and transcriptional activation and regulation of bone morphogenetic protein (BMP) and GNAS target genes. Developmental biology of BMP signaling.
KEY WORDS:
Bone formation, cell differentiation, human genetics, molecular biology, cell biology, developmental biology, gene expression, inherited diseases, bone, cartilage, bone morphogenetic protein, BMP, ACVR1, G-proteins, GNAS, FOP, POH.
DESCRIPTION OF RESEARCH:
Research in our laboratory is focused on genetic diseases of bone formation, mainly fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH). Both of these rare disorders are characterized by de novo formation of bone: in FOP, the ectopic bone forms in deep connective tissues such as muscle; and in POH, bone formation initiates within the skin. Our goals are to investigate the genetic causes of these conditions and the cellular pathways that are involved in the induction of bone development and formation, and to use this information to develop treatments for these and other disorders of bone.
With our identification of the mutated genes for POH and FOP, our experimental directions are focused on determining the functions of these genes and the consequences of the identified mutations.
POH is caused by heterozygous inactivating mutations in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS). Our data suggest that phenotypic expression of a GNAS mutation may be affected by genomic imprinting. GNAS is a complex gene that encodes multiple transcripts regulated by different promoters. Active areas of investigation include: genetics and epigenetics of GNAS and POH; the roles of GNAS expression in bone cell differentiation; and investigation of the signal transduction pathways mediated by GNAS proteins.
Linkage analysis of families with inheritance of FOP identified a common mutation (R206H) in the ACVR1 gene in patients with classic features of the disease. ACVR1 encodes a BMP type I receptor. Areas of investigation include the genetics and gene regulation of FOP, for example, loss of heterozygosity (LOH) within the candidate interval has been identified in one patient and may include a regulatory region for ACVR1; and recent studies examined the ACVR1 gene in patients with very severe or mild forms of FOP and identified novel ACVR1 mutations that suggest genotype-phenotype correlations. We are also investigating the effects of FOP ACVR1 mutations on the BMP signaling pathway and roles in cartilage and bone cell differentiation. Mouse and zebrafish models are being used to investigate the developmental biology of ACVR1 signaling in bone and cartilage as well as other tissues during vertebrate development.
In addition, we are using cell lineage-tracing analyses to investigate the source and identity of the cells that are induced to differentiate into cartilage and/or bone in FOP and POH. We are interested in identifying the earliest cellular events that occur during the induction of bone formation.
Translational studies and drug development are an increasing focus within the lab. Animal models for FOP and POH will be used to evaluate gene therapy and other strategies to treat these conditions.
LAB ROTATION PROJECTS FOR 2009-2010:
Rotation projects are available in most of the research areas described in the Research Summary. Specific projects will be discussed individually. Laboratory research is closely tied to clinical observation and patient care, and students are encouraged to have patient contact.
LAB PERSONNEL: (as of Summer 2009)
Collaborators: Frederick S. Kaplan MD, David Glaser MD, Robert J. Pignolo, MD, PhD
Students: Andria Culbert (CAMB); Andrew Smith (undergrad); Edwin Theosmy (undergrad)
Post-doc/Research Associates: Salin Chakkalakal PhD; Josef Kaplan PhD; Vitali Lounev PhD; Shengliang Zhang PhD; Haitao Wang PhD
Research Specialists: Bob Caron; Ruth McCarrick-Walmsley; Meiqi Xu; Deyu Zhang
Selected Publications
Kaplan, F.S., M. Xu, P. Seemann, M. Connor, D.L. Glaser, L. Carroll, P. Delai, E. Fastnacht-Urban, S.J. Forman, G. Gillessen-Kaesbach, J. Hoover-Fong, B. Köster, R.M. Pauli, W. Reardon, S-A. Zaidi, M. Zasloff, R. Morhart, S. Mundlos, J. Groppe, E.M. Shore : Classic and Atypical FOP Phenotypes are Caused by Mutations in the BMP Type I Receptor ACVR1. Human Mutation 30: 379-390, 2009.
Lounev, V.Y., R. Ramachandran, M.N. Wosczyna, M. Yananoto, A.D.A. Maidment, E.M. Shore, D.L. Glaser, D.J. Goldhamer, F.S. Kaplan : Identification of progenitor cells that contribute to heterotopic skeletogenesis. J. Bone Joint Surg. 91: 652-663, 2009.
Shore, E.M. and F.S. Kaplan: Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP). Bone 43: 427-433, August 2008.
Kaplan, F.S., M. Xu, D.L. Glaser, F. Collins, J.M. Connor, J. Kitterman, D. Sillence, E. Zackai, V. Ravitsky, M. Zasloff, A. Ganguly, E.M. Shore: Early diagnosis of fibrodysplasia ossificans progressiva (FOP). Pediatrics 121(5): 1295-1300, May 2008.
Huang, A.H., N.A. Motlekar, A. Stein, S.L. Diamond, E.M. Shore, R.L. Mauck : High-throughput screening for modulators of mesenchymal stem cell chondrogenesis. Annals of Biomedical Engineering 36: 1909-1921, 2008.
Adegbite, N.S, M. Xu, F.S. Kaplan, E.M. Shore*, R.J. Pignolo*: Clinical features, GNAS mutational analysis, and diagnostic criteria for progressive osseous heteroplasia (POH) and POH-like syndromes. Amer. J. Med. Genetics 146A(14): 1788-1796, 2008 Notes: *Equal contributors.
Groppe JC., Shore EM., Kaplan FS.: Functional Modeling of the ACVR1 (R206H) Mutation in FOP. Clinical Orthopaedics and Related Research 462: 87-92, September 2007.
Shore EM., Xu M., Feldman GJ., Fenstermacher DA., FOP International Research Consortium., Brown MA., Kaplan FS.: A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics 38(5): 525-7, May 2006.
Fiori JL., Billings PC., de la Pena LS., Kaplan FS., Shore EM.: Dysregulation of the BMP-p38 MAPK signaling pathway in cells from patients with fibrodysplasia ossificans progressiva (FOP). Journal of Bone & Mineral Research 21(6): 902-9, Jun 2006.
Shore EM., Ahn J., Jan de Beur S., Li M., Xu M., Gardner RJ., Zasloff MA., Whyte MP., Levine MA., Kaplan FS.: Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. New England Journal of Medicine 346(2): 99-106, Jan 2002.
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Last updated: 08/21/2009
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