Mechanistic and Therapeutic Studies of Initiation and Expansion for Genetic and Acquired Heterotopic Ossification

遗传性和获得性异位骨化的起始和扩展的机制和治疗研究

• 批准号: 10448133
• 负责人: Qian Cong
• 金额: $ 10.06万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448133
• 关键词: Affect; Automobile Driving; Binding; Bone Development; Bone Diseases; Cell Differentiation process; Chronic; Clinical; Complication; Data; Defect; Development; Disease; Ectopic Expression; Embryonic Development; Erinaceidae; Event; Family; Feedback; GTP-Binding Protein alpha Subunits, Gs; Genetic; Genetic Diseases; Genetic Transcription; Goals; Heterotopic Ossification; Human; In Vitro; Injury; Joints; Knowledge; Lead; Lesion; Ligands; Medical; Mesenchymal; Modeling; Molecular; Motion; Mus; Online Mendelian Inheritance In Man; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Outcome; Pathogenesis; Pathologic; Patients; Play; Progressive osseous heteroplasia; Promoter Regions; Puncture procedure; ROR1 gene; Recurrence; Regulation; Role; SHH gene; Sampling; Signal Transduction; Surgical complication; Tendon structure; Testing; Therapeutic Studies; Trauma; Traumatic injury; Up-Regulation; achilles tendon; acquired heterotopic ossification; bone; cartilage development; cell motility; cell type; cost; effective therapy; human disease; in vivo Model; insight; long bone; migration; mouse model; new therapeutic target; novel; null mutation; osteoblast differentiation; progressive myositis ossificans; rare genetic disorder; receptor; recruit; response; soft tissue; stem cell proliferation; stem cells; therapeutic target; therapeutically effective; transcription factor

Project Summary/Abstract Heterotopic ossification (HO) refers to extraskeletal pathological bone formation that occurs as a common complication after injury or as a manifestation of particular genetic disorders. However, limited by poor understanding of the underlying cellular and molecular mechanisms, there is currently no effective treatment and surgical eviction often results in recurrence. The overall goal of the project is to investigate cellular and molecular mechanisms underlying HO initiation and expansion and identify potential treatment targets for genetic and acquired HO. Our preliminary data suggests that in mouse models of progressive osseous heteroplasia (POH), a human disease caused by null mutations in GNAS that encodes Gαs, progressive expansion of ectopic bone was due to recruitment of surrounding wild-type cells. Mechanistically, Gnas-/- mesenchymal cells differentiate into osteoblasts and recruit wild-type cells to form bone by activating YAP, a transcription factor that regulates expression of Sonic hedgehog (Shh), which encodes a secreted ligand in the Hh family. Secreted SHH further induces YAP activation, thereby resulting in additional Shh expression and osteoblast differentiation in surrounding wild type cells. In human samples with acquired HO, upregulated YAP and HH signaling were also found, indicating the clinical importance of our findings. In our unpublished preliminary studies, we found upregulated Wnt5a expression in Gnas-/- SMPs in vitro and in HO lesions of POH mouse models in vivo. WNT5a not only regulates stem cell proliferation and enhances repopulation, but also plays an essential role in long bone and cartilage development during embryogenesis. Importantly, we found that Wnt5a expression was also controlled by YAP activation and was required for HO in both genetic and acquired HO. These findings lead to a central hypothesis that YAP and WNT5a are activated in a positive feedback loop to recruit progenitor cells for osteoblast differentiation in soft tissues, thereby promoting HO formation in both genetic and acquired HO mouse models. We will test these hypotheses in three aims. The first aim is to clarify the relationship between YAP and Wnt5a expression in ectopic bone formation in POH and test whether YAP and WNT5a interact in a positive feedback loop. The second aim is to illuminate the molecular mechanism in response to YAP and WNT5a in ectopic bone formation. The third aim is to investigate the contribution of WNT5a to ectopic bone formation in fibrodysplasia ossificans progressiva (FOP) and trauma-induced HO models. Taken together, these proposed studies will yield novel insights into a common cellular and molecular mechanism underlying initiation and expansion of distinct HO forms and highlight the importance of rare genetic disease studies in identifying a shared core pathological mechanism underlying a class of diseases.

项目摘要/摘要 异位骨化（HO）是指作为常见的骨架外病理骨形成 受伤后的并发症或特定遗传疾病的表现。 了解潜在的地窖和分子机制，目前尚无有效的治疗 手术驱逐通常会导致该项目的整体目标。 HO引发和扩张的基础机制，并确定遗传和 获得的HO。 由编码Gα的GNA中无效突变引起的人类疾病，异位骨的进行性扩张 是由于机理上募集了周围的野生型细胞。 通过激活YAP，进入成骨细胞并募集野生型细胞形成骨骼，YAP是调节的转录因子 Sonic刺猬（SHH）的表达，该刺猬（SHH）编码HH家族中的分泌配体。 诱导YAP激活，从而导致其他SHH表达和成骨细胞的区分 周围的野生型细胞在获得HO的人类样品中，上调YAP和HH信号 发现，表明我们的发现的临床重要性。 在体外和POH小鼠模型中，在GNA中的Wnt5a表达上调 不仅重新调节茎生纤维并增强重生，而且在长骨中起着至关重要的作用 和胚胎发生过程中的软骨发育。 由YAP激活控制，在遗传和获得的HO中都需要HO。 yap和wnt5a是一个积极反馈回路，以招募祖细胞的饲料 软组织中的成骨细胞分化，从而促进了两种遗传苯二进制HO小鼠的HO形成 我们将在三个目标中测试这些假设。 Wnt5a在POH中异位骨形成中的Wnt5a表达和测试Wnt5a在阳性中相互作用 反馈循环。 异位骨形成。 纤维状发育异常，Ossificans Progressiva（FOP）和创伤引起的HO模型。 研究将产生新的见解 扩展不同的HO形式，并强调了罕见遗传疾病研究在识别A中的重要性 共享一类疾病的核心病理机制。