Eileen M. Shore, Ph.D.Professor of Orthopaedic Surgery
Professor of Genetics
Cali and Weldon Professor of FOP Research
Newark, New Jersey
Post-Doctoral Fellow, Fox Chase Cancer Center, Philadelphia, PA
Ph.D. (Cell and Molecular Biology) University of Pennsylvania, Philadelphia, PA
M.A. (Biology) Indiana University, Bloomington, Indiana
B.S. (Biology) University of Notre Dame, South Bend, Indiana
AREAS OF SPECIAL INTEREST
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.
HONORS, AWARDS, and OTHER PROFESSIONAL ACTIVITIES
- 1995- Scientific Advisor, Progressive Osseous Heteroplasia Association
- 1998- Scientific Advisor, International Fibrodysplasia Ossificans Progressiva Association
- 2000 Advances in Mineral Metabolism Investigator Award
- 2002 Johnson & Johnson Focused Giving Award
- 2003-09 Board Member, Advances in Mineral Metabolism (AIMM)
- 2004-10 Editorial Board Member, Journal of Bone and Mineral Research
- 2005-12 Medical Faculty Senate Steering Committee, University of Pennsylvania School of Medicine
- 2006-10 Gender Equity Council Executive Committee, University of Pennsylvania School of Medicine
- 2007-11 NIH/NIAMS Skeletal Biology Development and Disease (SBDD) Study Section Member
- 2008- John Haddad Jr. Memorial Lecture Committee
- 2008 Alpha Omega Alpha Honor Medical Society Visiting Professor
- 2009-11 President, Advances in Mineral Metabolism Board of Directors
- 2012- Associate Editor, GENE
- 2012-15 Council Member, American Society of Bone and Mineral 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 important focus within the lab. Animal models for FOP and POH are used to evaluate strategies to treat these conditions.
PUBMED: Shore EM
PUBLICATIONS (Selected from ~90 peer-reviewed publications)
- Shore EM, Ahn J, Jan de Beur SM, Li M, Xu M, McKinlay Gardner RJ, Zasloff MA, Whyte MP, Levine MA, Kaplan FS (2002). Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia (POH). N. Engl. J. Med. 346, 99-106. PMID11784876
- Economides AN, DL Glaser, L Wang, X Liu, R Kimble, JP Fandl, JM Wilson, N Stahl, FS Kaplan, EM Shore (2003). In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification in the mouse. J. Bone Joint Surg. 85A, 2332-2342. PMID14668502
- Serrano de la Pena L, PC Billings, JL Fiori, FS Kaplan, EM Shore (2005) Fibrodysplasia ossificans progressiva (FOP), a disorder of ectopic osteogenesis, misregulates cell surface expression and trafficking of BMPRIA. J. Bone Min. Res. 20, 1168-1176. PMID15940369
- Fiori, J.L., P.C. Billings, L. Serrano de la Pena, F.S. Kaplan, and E.M. Shore (2006). Dysregulation of the BMP-p38 MAPK signaling pathway in fibrodysplasia ossificans progressiva (FOP) patients. J. Bone Mineral Res. 21 (6): 902-9. PMID16753021
- Shore, E.M., M. Xu, G.J. Feldman, D.A. Fenstermacher, The FOP International Research Consortium, M.A. Brown, and F.S. Kaplan (2006). A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics 38(5), 525-527. PMID16642017
- 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 (2008). Early diagnosis of fibrodysplasia ossificans progressiva (FOP). Pediatrics. 121: e1295-1300. PMID18450872
- Adegbite, N.S, M. Xu, F.S. Kaplan, E.M. Shore, R.J. Pignolo (2008). Clinical features, GNAS mutational analysis, and diagnostic criteria for progressive osseous heteroplasia (POH) and POH-like syndromes. Amer. J. Med. Genet. 146A(14): 1788-1796. PMID18553568
- 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. Koster, R.M. Pauli, W. Reardon, S-A. Zaidi, M. Zasloff, R. Morhart, S. Mundlos, J. Groppe, E.M. Shore (2009). Classic and Atypical FOP Phenotypes are Caused by Mutations in the BMP Type I Receptor ACVR1. Human Mutation 30, 379-390. PMID19085907
- 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 (2009). Fibrodysplasia ossifcans progressiva ACVR1 R206H mutation activates BMP-independent chondrogenesis and ventralization of zebrafish embryos. J. Clin. Invest. 119, 3462-3472. PMID19855136
- Shore, E.M. and F.S. Kaplan (2010). Inherited Human Diseases of Heterotopic Bone Formation. Nature Reviews Rheumatology 6, 518-527. PMID20703219
- Medici, D., E.M. Shore, V.Y. Lounev, F.S. Kaplan, R. Kalluri, and B.R. Olsen (2010). Conversion of vascular endothelial cells into multipotent stem-like cells. Nature Medicine 16, 1400-1406. PMID21102460
- Schimmel, R.J., S.G.M.A. Pasmans, M. Xu, S.A.E. Stadhouders-Keet, E.M. Shore, F.S. Kaplan, N.M. Wulffraat (2010). GNAS-associated disorders of cutaneous ossification: two different clinical presentations. Bone 46(3), 868-872. PMID: 19900597
- Groppe, J.C., J. Wu, E.M. Shore, F.S. Kaplan (2011). In vitro analysis of the Dysregulated R206H ALK2 kinase-FKBP12 interaction associated with heterotopic ossification in FOP. Cell Tissues Organs 194:291-295. PMID: 21525719
- Kan, L., V.Y. Lounev, R.J. Pignolo, L. Duan, Y. Liu, S.R. Stock, T.L. McGuire, B. Lu, N.P. Gerard, E.M. Shore, F.S. Kaplan and J.A. Kessler (2011). Substance P signaling mediates BMP-dependent heterotopic ossification. J. Cellular Biochemistry 112(10), 2759-2772. PMID: 21748788
- Pignolo, R.J., M. Xu, E. Russell, A. Richardson, J. Kaplan, P.C. Billings, F.S. Kaplan, E.M. Shore (2011). Heterozygous inactivation of Gnas confers enhanced osteogenic differentiation and formation of heterotopic ossification. J. Bone Miner. Res. 26, 2647-2655. PMID: 21812029
- Kaplan, J., F.S. Kaplan, and E.M. Shore (2012). Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting. Gene Therapy. 19, 786-790. PMID: 22011642
- Shore, E.M. (2012). Fibrodysplasia ossificans progressiva (FOP): A human genetic disorder of extra-skeletal bone formation, or - How does one tissue become another? WIREs Dev Biol 1, 153-165. PMID: 22408652Selected for Inaugural Issue.
- Liu, J., E. Russell, D. Zhang, F.S. Kaplan, R.J. Pignolo, and E.M. Shore (2012). Paternally inherited Gsa mutation impairs adipogenesis and potentiates a lean phenotype in vivo. Stem Cells 30, 1477-1485. PMID: 22511293
- Chakkalakal, S. A., D. Zhang, A.L. Culbert, M.R. Convente, R.J. Caron, A.C. Wright, A.D.A. Maidment, F.S. Kaplan, and E.M. Shore (2012). An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J. Bone Min. Res. 27, 1746-1756. PMID: 22508565
- Zhang, S. F.S. Kaplan, E.M. Shore (2012). Different roles of Gnas and cAMP signaling during early and late stages of osteogenic differentiation. Hormone Metab. Res. 44, 724-731. PMID: 22903279