Novel Zebrafish Models for Human Fibrodysplasia Ossificans Progressiva

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Project Summary/Abstract Craniofacial and skeletal development and homeostasis is the culmination of a complex interplay between a surprisingly large and growing number of tissues, components in the blood and vasculature, the immune response and growth factor signaling. Although knowledge of the complex signaling pathways resulting in human mineralized tissue diseases has improved over the past few decades, a detailed understanding of the majority of human mineralized tissue diseases remains elusive. Here we propose to use newly created transgenic zebrafish lines expressing constitutively active (CA) Alk8/ACVR1 genes as models for human Fibrodysplasia Ossificans Progressiva (FOP). FOP is a fatal disease characterized by the progressive heterotopic ossification (HO) of soft tissues over time eventually resulting in death at age ~40 years. The objectives of the proposed studies are to: 1) establish zebrafish models for FOP; 2) identify the progenitor cells that ultimately contribute to HO in humans with FOP; and 3) exploit FOP zebrafish to identify small molecule inhibitors of FOP. Our methods include newly created transgenic zebrafish lines expressing constitutively active (CA) Alk8/ACVR1 as models for human Fibrodysplasia Ossificans Progressiva (FOP). Transgenesis approaches will be used to label and lineage trace four cell types implicated in human FOP, and small molecule screens will be interrogated to identify inhibitors of activating Alk8/ACVR1 mutations. Our published expertise in molecular genetic characterizations of zebrafish mineralized tissue development and disease, strong preliminary data, and team of clinical, developmental, and immunological investigators supports our ability to accomplish the proposed Aims. We anticipate that the completion of the proposed studies will result in significantly improved knowledge of the molecular basis of FOP, which will facilitate the generation of effective targeted therapies for the prevention and/or cure of this debilitating mineralized tissue disease. In addition, elucidation of the molecular signals directing HO may also be used to devise more effective strategies to regenerate bone in a controlled and directed manner. The significance of the proposed studies and relevance to public health includes the fact that skeletal and craniofacial defects occur in as many as 1 in 700 live births in the United States alone, making this a serious health issue. In addition, HO is observed in other human diseases such as calcific heart valve disease and atherosclerosis, making these studies of potential benefit for numerous diseases associated with the aging populations.