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.
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. Our current work includes:
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 and fat 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 variable expressivity of FOP, for example, recent studies examined the ACVR1 gene in patients with very severe or mild forms of FOP and identified novel ACVRl 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. Recently initiated studies are investigating the cellular and tissue events that occur prior to aberrant cell differentiation to form bone.
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.
PUBMED: Shore EM
LAB ROTATION PROJECTS FOR 2012-2013:
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 Spring 2012)
Collaborators: FrederickS. Kaplan MD, Robert J. Pignolo, MD, PhD
Students: Andria Culbert (CAMB); Michael Convente (CAMB); Will Towler (CAMB); Edwin Theosmy (post-bac)
Post-doc/Research Associates: Salin Chakkalakal PhD; Julia Haupt PhD; Josef Kaplan PhD; Vitali Lounev PhD; Girish Ramaswamy PhD; Haitao Wang PhD
Research Specialists: Bob Caron; Ruth McCarrick-Walmsley; Meiqi Xu; Deyu Zhang
Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, Maidment AD, Kaplan FS, Shore EM.
: An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva.
J Bone Miner Res 27(8): 1746-1756, April 16 2012.
Shore, E.M. : Fibrodysplasia ossificans progressiva (FOP): A human genetic disorder of extra-skeletal bone formation, or - How does one tissue become another? Wiley Interdiscip Rev Dev Biol. Selected for Inaugural Issue. 1(1): 153-165, January 2012.
Liu JJ, Russell E, Zhang D, Kaplan FS, Pignolo RJ, Shore EM.
: Paternally-Inherited Gsα Mutation Impairs Adipogenesis and Potentiates a Lean Phenotype In vivo.
Stem Cells 30(7): 1477-1485, Jul 2012.
Pignolo, R.J., M. Xu, E. Russell, A. Richardson, J. Kaplan, P.C. Billings, F.S. Kaplan, E.M. Shore.: Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification.
JBMR 26(11): 2647-2655, November 2011.
Kaplan, J., F.S. Kaplan, and E.M. Shore : Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting. Gene Therapy 19(7): 786-790, October 2012.
Shore, E.M. and F.S. Kaplan : Inherited Human Diseases of Heterotopic Bone Formation. Nature Reviews Rheumatology 6(9): 518-527, September 2010.
Medici, D., E.M. Shore, V.Y. Lounev, F.S. Kaplan, R. Kalluri, and B.R. Olsen : Conversion of vascular endothelial cells into multipotent stem-like cells. Nature Medicine 16(12): 1400-1406, December 2010 Notes: Epub 2010 Nov 21
Erratum in: Nat Med 2011 Apr;17(4):514
Shen, Q., S.C. Little, M. Xu, J. Haupt, C. Ast, T. Katagiri, S. Mundlos, P. Seemann, F.S. Kaplan, M.C. Mullins, E.M. Shore.: Fibrodysplasia ossifcans progressiva ACVR1 R206H mutation activates BMP-independent chondrogenesis and ventralization of zebrafish embryos. J. Clin. Invest 119(11): 3462-3472, November 2009.
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): 525-527, May 2006.
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Last updated: 07/14/2017
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