Perelman School of Medicine at the University of Pennsylvania

McKay Orthopaedic Research Laboratory

Shore Laboratory

Welcome to Shore Laboratory

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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.