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.

项目摘要/摘要 异位骨化(HO)是一种肌肉和骨骼外骨骼形成的多种病理过程。 软组织，可分为遗传型和非遗传型(后天)HO。一场罕见的毁灭性的 遗传性HO的形式是进行性纤维发育不良骨化症(FOP)，由 激活素受体A型(ACVR1)基因。在非遗传性形式中，HO经常出现在肌腱和 韧带，通常是在软组织创伤、矫形外科手术、与战斗有关的爆炸和 伯恩斯。目前仍没有治疗HO的有效药物。我们的长期目标是破译 研究HO的发病机制(S)，为HO的临床治疗提供新的策略。总体目标是 (I)阐明纤毛在骨形态发生蛋白(BMP)信号通路中的基本作用和(Ii) 使用新的HO模型确定其功能。中心假说是初级纤毛在 正常和致病BMP信号的转导及其病理生理机制的调控 遗传性和非遗传性何氏。其基本原理是，遗传性和非遗传性HO形成都是 主要由BMP信号通路介导。然而，它仍然难以捉摸，在哪里和如何BMP信号 在细胞中被转导和调节。初生纤毛是从纤毛表面伸出的天线状结构 细胞，对许多细胞信号通路的正确转导至关重要。功能失调的主纤毛 导致一系列人类疾病，统称为纤毛病。我们的初步数据显示 初级纤毛在传递正常和致病的BMP信号中发挥核心作用，并调节 HO形成的病理生理机制(S)。核心假设将通过以下几个方面进行检验 具体目标：1)确定控制正常和致病BMP的纤毛成分/途径 信号通路。2)确定我们新建立的非遗传性纤毛的调节功能 烧伤/肌腱切断诱导的HO小鼠模型具有取消的纤毛信号通路。3)确定目标 用于抑制纤毛相关通路，作为遗传性和非遗传性HO治疗的基础。 这项申请中提出的研究是创新的，因为我们的初步数据表明，FOP和 也许其他HO情况代表纤毛介导的疾病，这为 未来的疗法。从机制上讲，我们将系统地阐明纤毛在BMP信号中的作用。 特别是与HO小鼠模型相关联的。这项拟议的研究意义重大，从科学上讲，它将 建立一个新的范式，即初级纤毛在软骨形成中BMP信号转导中起核心作用 和/或最终导致遗传性和非遗传性HO的成骨。在临床上，靶向 纤毛介导的BMP途径是一种尚未探索的治疗策略，不仅可用于FOP，而且可用于FOP 也适用于其他更常见的HO形式，如创伤后HO。