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Principal Investigator: Haitao Wang
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $410,535
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
PROJECT SUMMARY/ABSTRACT
Heterotopic ossification (HO), a diverse pathologic process of formation of extraskeletal bone in muscle and
soft tissues, can be classified into hereditary and nonhereditary (acquired) HO types. A rare and devastating
form of hereditary HO is fibrodysplasia ossificans progressiva (FOP), caused by gain-of-function mutations in
Activin receptor A type I (Acvr1) gene. In the nonhereditary forms, HO frequently occurs in tendons and
ligaments and is commonly incited upon soft tissue trauma, orthopedic surgeries, combat-related blasts, and
burns. There are currently still no effective drugs to treat HO. Our long-term goal is to decipher the
mechanism(s) of HO and develop novel strategies for the clinical treatment of HO. The overall objectives are to
(i) elucidate the essential roles of cilia on the Bone morphogenetic protein (BMP) signaling pathway and (ii)
determine its function using novel HO models. The central hypothesis is that primary cilia play central roles in
transducing normal and pathogenic BMP signaling and regulating the pathophysiological mechanism of both
hereditary and nonhereditary HO. The rationale is that both hereditary and nonhereditary HO formation are
primarily mediated by the BMP signaling pathway. However, it remains elusive where and how BMP signaling
is transduced and regulated in cells. Primary cilia are antenna-like structures protruding from the surface of
cells and are critical for proper transduction of many cellular signaling pathways. Dysfunctional primary cilia
result in a broad spectrum of human diseases collectively termed ciliopathies. Our preliminary data suggest
that primary cilia play central roles in transducing normal and pathogenic BMP signaling and regulate the
pathophysiological mechanism(s) of HO formation. The central hypotheses will be tested by pursuing these
specific aims: 1) Determine the ciliary components/pathways that govern normal and pathogenic BMP
signaling pathways. 2) Determine the regulatory function of cilia in our newly established nonhereditary
burn/tenotomy-induced HO mouse models that have abrogated ciliary signaling pathways. 3) Identify targets
for inhibition of cilium-related pathways as the basis for treatments in hereditary HO and nonhereditary HO.
The research proposed in this application is innovative because our preliminary data suggest that FOP and
perhaps other HO conditions represent cilium-mediated disorders, which provides a novel perspective for
future therapies. Mechanistically, we will systematically elucidate the function of cilia on BMP signaling
specifically as associated with HO mouse models. The proposed research is significant, and scientifically it will
build a new paradigm that primary cilium plays a central role in transducing BMP signaling in chondrogenesis
and/or osteogenesis that ultimately results in both hereditary and nonhereditary HO. Clinically, targeting the
cilia-mediated BMP pathway is an unexplored therapeutic strategy that could be applied not only for FOP but
also for other more common forms of HO, such as post-traumatic HO.
Terms: <ACTRI><ACVR1><ACVR1 gene><ACVRLK2><ALK2><ARL3><ARL3 gene><Activin A Receptor, Type II-Like Kinase 2 Gene><Activin Receptor><Activin Receptor-Like Kinase 2 Gene><Activin Receptor-Like Kinases><Animal Model><Animal Models and Related Studies><Autoregulation><Autosomal Recessive Medullary Cystic Disease><BMP4><Binding><Blast Injuries><Body Tissues><Bone Formation><Bone Morphogenetic Protein Gene><Bone Morphogenetic Proteins><Burn injury><Burns><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Membrane Extensions><Cell Membrane Projections><Cell Membrane Protrusions><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell Surface Extensions><Cell Surface Projections><Cell Surface Protrusions><Cells><Chondrogenesis><Cilia><Classification><Clinical><Clinical Treatment><Complex><Connective Tissue><Data><Development><Disease><Disorder><Drugs><Dysfunction><EYDF><Ectopic Ossification><FK-506-Binding Protein><FK506 Binding Proteins><FK506 binding protein 5><FKBP><FKBP Rotamase><FKBP51><FKBP54><Fibrodysplasia Ossificans Progressiva><Flare><Functional disorder><Functional impairment><Future><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Goals><Hereditary><Heterotopic Ossification><Homeostasis><Human><Immobilization><In Vitro><Inherited><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ligaments><Ligands><Link><Mediating><Medication><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Mission><Modeling><Modern Man><Modernization><Molecular><Molecular Interaction><Muscle><Muscle Tissue><Musculoskeletal><Mutation><NIH><NPHP><National Institutes of Health><Nephronophthisis><Orthopedic Surgery><Osteogenesis><Pathogenicity><Pathologic><Pathologic Ossification><Pathologic Processes><Pathological Ossification><Pathological Processes><Pathway interactions><Patients><Pharmaceutical Preparations><Phosphorylation><Physiological Homeostasis><Physiopathology><Play><Prevention><Primary Tooth><Procedures><Progenitor Cells><Protein Phosphorylation><Receptor Protein><Research><Role><SKR1><Sensory><Short interfering RNA><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Skeletal Development><Small Interfering RNA><Structure><Surface><System><Systematics><Tacrolimus Binding Proteins><Temporary Tooth><Tendon structure><Tendons><Testing><Therapeutic><Tissues><Tooth Cell><Trauma><Type I Gene Activin A Receptor><United States National Institutes of Health><acquired heterotopic ossification><activin A><biological signal transduction><bone><bone morphogenic protein><bone tissue formation><burned><cell sorting><ciliopathy><combat><deciduous tooth><developmental><disability><drug/agent><erythroid differentiation factor><erythroid differentiation protein><experiment><experimental research><experimental study><experiments><gain of function mutation><genetic condition><genetic disorder><genome mutation><homo-activin A><human disease><in vivo><in vivo Model><inhibitor><injuries><innovate><innovation><innovative><interventional strategy><lipid based nanoparticle><lipid nanoparticle><loss of function><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><model of animal><mouse model><murine model><muscular><mutant><myositis ossificans progressiva><new approaches><non-genetic><nongenetic><novel><novel approaches><novel strategies><novel strategy><orthopedic freezing><pathophysiology><pathway><prevent><preventing><progressive myositis ossificans><progressive ossifying myositis><receptor><response><siRNA><skeletal><social role><soft tissue><spatiotemporal><stem cells><tacrolimus binding protein 5><tissue trauma><treatment strategy><trial regimen><trial treatment>