the Gut Microbiome as a Disease Modifier of Heterotopic Ossification

肠道微生物组作为异位骨化的疾病调节剂

• 批准号: 10624949
• 负责人: EDWARD C HSIAO
• 金额: $ 66.07万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624949
• 关键词: ACVR1 gene; Ablation; Affect; Anti-Inflammatory Agents; Antibiotics; Antigens; Bacteria; Biological Assay; Blood; Bone Marrow; Cells; Cessation of life; Chemotaxis; Chemotaxis Induction; Circulation; Clinical; DNA Sequence Alteration; Data; Diet; Dietary Factors; Dietary Supplementation; Disease; Disease Outcome; Disease Progression; Environmental Risk Factor; Flare; Genetic; Genetic Diseases; Germ-Free; Gnotobiotic; Goals; Heterotopic Ossification; Home; Human; Human Microbiome; Immobilization; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injections; Innate Immune System; Intramuscular; Joints; Knowledge; Life; Macrophage; Macrophage Activation; Measures; Methods; Microfluidics; Mus; Muscle; Musculoskeletal Diseases; Mutation; Myelogenous; Orthopedic Surgery; Osteogenesis; Pain; Patients; Phase; Phenotype; Point Mutation; Process; Production; Role; Sampling; Severities; Siblings; Signal Transduction; Skeletal Muscle; Symptoms; System; Testing; Transplantation; activin A; bone morphogenetic protein receptors; cell motility; chemokine; chronic pain; cohort; commensal microbes; cytokine; fecal microbiome; fecal transplantation; gut microbiome; gut microbiota; in vivo; induced pluripotent stem cell; microbial; microbial community; microbiome; microbiota; migration; monocyte; mouse model; musculoskeletal injury; non-genetic; novel; novel therapeutic intervention; premature; prevent; probiotic supplementation; progressive myositis ossificans; receptor; repaired; response; soft tissue; stool sample; systemic inflammatory response

Fibrodysplasia ossificans progressiva (FOP) is a currently untreatable genetic 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. This project will explore the role of microbiota in inflammation and HO in FOP. Aim 1: Identify the modulatory roles of the gut microbiome in disease progression in FOP mice. Advanced gnotobiotic methods and germ-free FOP mice colonized with defined pro- or anti-inflammatory microbiota. We will also test whether dietary supplementation with probiotic bacteria or compounds that tighten gut barrier integrity will reduce FOP progression. Aim 2: Identify the role of the microbiome in chemokine-dependent polarization and migration of MCYs and macrophages that enhance EHO in FOP. These studies will determine whether the gut microbiome exacerbates EHO in FOP by sensitizing bone marrow MCYs/MΦs to chemokine-induced chemotaxis and increasing the expression of proinflammatory chemokines during flares, which together increase infiltration and inflammatory polarization of MCYs and MΦs. Aim 3: Establish the relationship between gut microbiota, monocyte/macrophage activation, and severity of FOP flares in humans and mice. These studies will determine if the gut microbial community in patients with FOP modulates disease progression by increasing systemic inflammatory tone, thus priming MCY/MΦ activation. Stool samples will be collected from patients with FOP, microbiota analyzed and correlated with FOP disease outcomes. We will also colonize germ-free FOP mice with the microbiome of human FOP patients by fecal transplant in a human microbiome-association (HMA) approach. Finally, we will use a new microfluidic culture system to determine the responses of human iPSC derived M1- and M2-like MΦs from control and FOP patients to defined microbiome antigens.These studies will provide novel mechanistic understanding of how the gut microbiome affects HO and provide a basis for testing how gut microbiome manipulation may augment treatment of FOP and non-genetic HO.

进行性骨化性纤维发育不良（FOP）是一种目前无法治疗的遗传性疾病，其中骨骼肌 修复被重定向到软骨内骨形成（异位骨化，HO），导致疼痛、肌肉 破坏和关节融合，导致逐渐固定并最终过早死亡。这个项目 将探讨微生物群在 FOP 中炎症和 H2O 中的作用。目标 1：确定肠道的调节作用 微生物组在 FOP 小鼠疾病进展中的作用。先进的无菌方法和无菌 FOP 小鼠 定殖有明确的促炎或抗炎微生物群。我们还将测试膳食补充剂是否 益生菌或加强肠道屏障完整性的化合物将减少 FOP 的进展。目标 2：确定 微生物组在 MCY 和巨噬细胞的趋化因子依赖性极化和迁移中的作用 增强 FOP 中的 EHO。这些研究将确定肠道微生物组是否通过以下方式加剧 FOP 中的 EHO： 使骨髓 MCYs/MΦs 对趋化因子诱导的趋化作用敏感并增加 耀斑期间的促炎趋化因子，它们共同增加了炎症的浸润和极化 MCY 和 MΦ。目标 3：建立肠道微生物群、单核细胞/巨噬细胞之间的关系 人类和小鼠中 FOP 耀斑的激活和严重程度。这些研究将确定肠道微生物是否 FOP 患者的社区通过增加全身炎症张力来调节疾病进展，从而 引发 MCY/MΦ 激活。将从 FOP 患者身上采集粪便样本，进行微生物群分析并 与 FOP 疾病结果相关。我们还将用人类微生物组移植无菌 FOP 小鼠 采用人类微生物组协会 (HMA) 方法对 FOP 患者进行粪便移植。最后，我们将使用一个新的 微流体培养系统，用于确定对照中人类 iPSC 衍生的 M1 和 M2 样 MΦ 的反应 和 FOP 患者确定的微生物组抗原。这些研究将为 肠道微生物组如何影响 HO，并为测试肠道微生物组操作如何增强 HO 提供基础 FOP 和非遗传性 HO 的治疗。