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

基本信息

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
项目类别：
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

项目摘要

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.

纤维浮肿骨（FOP）是目前不可治疗的遗传疾病，其中骨骼肌肉修复被重定向到内侧软骨形成（异位骨化，HO），导致疼痛，肌肉破坏和联合融合，导致渐进式固定并最终过早死亡。这个项目将探索微生物群在炎症中的作用，而HO在FOP中的作用。目标1：确定肠道的调节作用 FOP小鼠疾病进展的微生物组。先进的gnotobiotic方法和无菌FOP小鼠用定义的促疾病或抗炎微生物群定殖。我们还将测试是否补充饮食收紧肠道屏障完整性的益生菌细菌或化合物将降低FOP的进展。目标2：确定微生物组在趋化因子依赖性极化以及MCYS和巨噬细胞的迁移中的作用增强FOP中的EHO。这些研究将确定肠道微生物组是否通过将骨髓MCys/Mφs敏感到趋化因子诱导的趋化性，并增加耀斑期间促炎的趋化因子，加上增加浸润和炎症极化 MCYS和MφS。 AIM 3：建立肠道菌群，单核细胞/巨噬细胞之间的关系人类和小鼠的激活和FOP耀斑的严重程度。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性炎症性张力调节疾病进展，因此启动MCY/Mφ激活。将从FOP患者，分析微生物群的患者那里收集粪便样品，并与FOP疾病结局相关。我们还将用人类的微生物组殖民无菌FOP小鼠通过人类微生物组关联（HMA）方法中的粪便移植患者。最后，我们将使用新的微流体培养系统，以确定从对照中衍生的M1和M2样Mφ的响应和FOP患者可以定义的微生物组抗原。这些研究将提供新的机械理解肠道微生物组如何影响HO并为测试肠道微生物组的操纵如何增强提供基础 FOP和非遗传HO的处理。