The contribution of innate immunity to heterotopic ossification in fibrodysplasia ossificans progressiva

先天免疫对进行性骨化性纤维发育不良异位骨化的贡献

• 批准号: 10249238
• 负责人: Daniel S Perrien
• 金额: $ 42.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249238
• 关键词: ACVR1 gene; Address; Agonist; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Biological Assay; Bone Morphogenetic Proteins; Cells; Cessation of life; Chemicals; Chondrocytes; Chondrogenesis; Coculture Techniques; Data; Development; Disease; Feedback; Fibrosis; Flare; Functional disorder; Growth; Heterotopic Ossification; Immobilization; Immune; In Vitro; Individual; Inflammation; Inflammatory; Injury; Intramuscular; Joints; Lead; Lesion; Link; MAP Kinase Gene; Mediating; Mus; Muscle; Mutation; Myelogenous; Myeloid Cells; Natural Immunity; Osteogenesis; Pain; Patients; Point Mutation; Rare Diseases; Resistance; Role; STING agonists; Signal Pathway; Signal Transduction; Signaling Protein; Skeletal Muscle; Source; Swelling; Systemic infection; TNF gene; Time; Tissues; Transforming Growth Factor beta; activin A; bone morphogenetic protein receptor type I; cytokine; early childhood; edg-1 Protein; genetic approach; inhibitor/antagonist; injured; insight; interstitial; macrophage; monocyte; muscle regeneration; mutant; nanoparticle; new therapeutic target; p38 Mitogen Activated Protein Kinase; premature; prevent; progenitor; progressive myositis ossificans; receptor; repaired; response; tissue repair; tumor

Fibrodysplasia ossificans progressiva (FOP) is a rare, currently untreatable, congenital disease in which skeletal muscle repair is redirected to endochondral bone formation (heterotopic ossification, HO) causing pain, muscle destruction, and joint fusion, leading to progressive immobilization and eventually premature death. FOP is caused by a mutation in Alk2 (most commonly R206H) that renders the receptor sensitive to aberrant activation by Activin A (ActA). However, the “flares” that lead to HO appear to be initiated by inflammatory insults, and HO can be reduced in FOP mice by depletion of inflammatory innate immune cells including macrophages. Fibroadipoprogenitors (FAPs), residing in the muscle interstitium appear to be the critical precursors of chondrocytes in FOP. However, in healthy muscle repair, macrophages secrete TNFα at a critical time to trigger apoptosis of FAPs. The fact that FAPs survive and differentiate into chondrocytes suggests their interaction with macrophages is disrupted in FOP. Therefore, this proposal will explore the hypothesis that pro-inflammatory M1-like and anti-inflammatory M2-like macrophages are critical sources of cytokines that enable survival and expansion of the chondrogenic fibroadipoprogenitors in FOP. Specifically, it seeks to determine whether macrophages are a critical source of ActA and what signals pathways in FAPS are disrupted to block their normal apoptotic fate. These studies will be the first to explore the mechanisms by which macrophages interact with chondrogenic FAPs to support chondrogenesis and HO, and they will provide critical insights to the early stages of FOP flares.

纤维浮肿骨（FOP）是一种罕见的，目前不可治疗的先天性疾病，其中 骨骼肌修复被重定向到内侧软骨骨形成（异位骨化，HO），导致 疼痛，肌肉破坏和关节融合，导致进行性固定，最终过早 死亡。 FOP是由ALK2（最常见的R206H）突变引起的，该突变使接收器敏感 激活素A（ACTA）的异常激活。但是，导致HO外观的“耀斑”由 炎症性损伤和HO可以通过炎症先天免疫细胞的耗竭来减少FOP小鼠 包括巨噬细胞。纤维富生构基（FAPS），位于肌肉间质外观中 FOP中软骨细胞的关键前体。但是，在健康的肌肉修复中，巨噬细胞秘密TNFα在 触发FAP凋亡的关键时间。 FAP生存并分化为软骨细胞的事实 表明它们与巨噬细胞的相互作用在FOP中被破坏。因此，该建议将探索 假设促炎性M1样和抗炎M2样巨噬细胞是关键来源 能够在FOP中生存和扩展软骨肌源基因的细胞因子。具体来说， 它试图确定巨噬细胞是否是ACTA的关键来源以及FAPS中哪些信号途径 被破坏以阻止其正常的凋亡命运。这些研究将是第一个通过 哪些巨噬细胞与软骨的FAP相互作用，以支持软骨和HO，它们将提供 FOP耀斑早期阶段的关键见解。