The essential roles of primary cilia in heterotopic ossification

初级纤毛在异位骨化中的重要作用

• 批准号: 10734116
• 负责人: Haitao Wang
• 金额: $ 42.32万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734116
• 关键词: ACVR1 gene; ARL3 gene; Activin Receptor; Animal Model; BMP4; Binding; Blast Injuries; Bone Morphogenetic Proteins; Burn injury; Cell Separation; Cell Surface Extensions; Cells; Chondrogenesis; Cilia; Classification; Clinical; Clinical Treatment; Complex; Connective Tissue; Data; Development; Disease; FK506 binding protein 5; Flare; Functional disorder; Future; Genes; Genetic; Genetic Diseases; Goals; Heterotopic Ossification; Homeostasis; Human; Immobilization; In Vitro; Inherited; Injury; Intervention; Ligaments; Ligands; Link; Mediating; Mesenchymal Stem Cells; Mission; Modeling; Modernization; Molecular; Muscle; Musculoskeletal; Mutation; Nephronophthisis; Orthopedic Surgery; Osteogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Play; Prevention; Procedures; Research; Role; Sensory; Signal Pathway; Signal Transduction; Signaling Protein; Skeletal Development; Skeletal bone; Small Interfering RNA; Structure; Surface; System; Tacrolimus Binding Proteins; Tendon structure; Testing; Therapeutic; Tissues; Tooth Cell; Trauma; United States National Institutes of Health; acquired heterotopic ossification; activin A; bone; ciliopathy; combat; deciduous tooth; disability; experimental study; functional disability; gain of function mutation; human disease; in vivo; in vivo Model; inhibitor; innovation; lipid nanoparticle; loss of function; mouse model; mutant; non-genetic; novel; novel strategies; prevent; progressive myositis ossificans; receptor; response; skeletal; soft tissue; spatiotemporal; stem cells; tissue trauma; treatment strategy

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.

项目总结/文摘