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.

项目概要/摘要 异位骨化（HO）是肌肉和骨骼中骨外骨形成的多种病理过程。 软组织可分为遗传性和非遗传性（获得性）HO 类型。罕见且具有毁灭性的 遗传性 HO 的一种形式是进行性骨化性纤维发育不良 (FOP)，由功能获得性突变引起 激活素 A 型受体 (Acvr1) 基因。在非遗传性形式中，HO 经​​常发生在肌腱和肌腱中。 韧带损伤，通常因软组织创伤、整形外科手术、战斗相关爆炸以及 烧伤。目前尚无治疗HO的有效药物。我们的长期目标是破译 HO 的机制并开发 HO 临床治疗的新策略。总体目标是 (i) 阐明纤毛对骨形态发生蛋白 (BMP) 信号通路的重要作用，以及 (ii) 使用新颖的 HO 模型确定其功能。中心假设是初级纤毛在 转导正常和致病性 BMP 信号传导并调节两者的病理生理机制 遗传性和非遗传性 HO。基本原理是遗传性和非遗传性 HO 的形成都是 主要由 BMP 信号通路介导。然而，BMP 信号传导在何处以及如何进行仍然难以捉摸。 在细胞中被转导和调节。初级纤毛是从表面突出的天线状结构 细胞，对于许多细胞信号通路的正确转导至关重要。初级纤毛功能失调 导致广泛的人类疾病，统称为纤毛病。我们的初步数据表明 初级纤毛在转导正常和致病性 BMP 信号传导并调节 H2O 形成的病理生理机制。中心假设将通过追求这些来检验 具体目标：1) 确定控制正常和致病性 BMP 的睫状成分/通路 信号通路。 2）确定纤毛在我们新建立的非遗传性细胞中的调节功能 烧伤/腱切断术诱导的 HO 小鼠模型消除了纤毛信号通路。 3）确定目标 抑制纤毛相关途径，作为遗传性 HO 和非遗传性 HO 治疗的基础。 本申请中提出的研究具有创新性，因为我们的初步数据表明 FOP 和 也许其他 HO 条件代表了纤毛介导的疾病，这提供了一个新的视角 未来的治疗方法。从机制上，我们将系统地阐明纤毛对BMP信号传导的功能 特别是与 HO 小鼠模型相关。拟议的研究意义重大，从科学角度来看，它将 建立初级纤毛在软骨形成中转导 BMP 信号传导中发挥核心作用的新范例 和/或成骨，最终导致遗传性和非遗传性 HO。临床上，针对 纤毛介导的 BMP 通路是一种尚未探索的治疗策略，不仅可以应用于 FOP，还可以应用于 也适用于其他更常见的 HO 形式，例如创伤后 HO。