Role of the CD47 Pathway in Rheumatoid Arthritis Pathogenesis and Treatment

项目摘要 类风湿性关节炎（RA）是一种慢性进行性过程， 发病率和死亡率。RA是由炎症和基质病理驱动的，而 目前的疗法改善炎症，没有有效的治疗靶向成纤维细胞 和骨病理学的研究CD 47通路可以影响免疫细胞的吞噬作用， 通过SIRP-a信号传导和通过TSP-1信号传导的基质病理学。本研究将定义 CD 47信号传导在患者生物标本和关节炎小鼠模型中的作用，并评估 抗CD 47疗法和生物制剂组合在RA中的效用。我们的核心假设是， CD 47在RA发病机制中至关重要，其阻断将改善或逆转 炎性关节炎和骨质侵蚀。我们将通过三个具体的测试来验证这一假设。 目标。目的1将描述通过TSP-1和SIRP-a的CD 47信号传导在肿瘤细胞中的作用。 RA患者通过组织学分析、单细胞RNA测序和滑膜类器官 cultures.目的2将通过评估CD 47是否是炎症性关节炎所必需的， 在诱导关节炎后，CD 47缺陷小鼠的关节炎、骨结果和细胞功能。 目的3将确定CD 47抑制剂与生物疗法联合的有效性 首先使用体外药物筛选治疗关节炎，然后测试最有希望的 体内候选疗法。这项研究的意义重大，因为它将大大 提高对RA生物学的理解，因为它有可能识别新的 可以治疗RA中的炎症和间质途径的治疗策略。

Project Summary Rheumatoid arthritis (RA) represents a chronic progressive process which leads to significant morbidity and mortality. RA is driven by both inflammatory and stromal pathologies, and while current therapies improve inflammation, there are not effective treatments targeting fibroblasts and bone pathology in RA. The CD47 pathway can affect both immune cell phagocytosis through SIRP-a signaling and stromal pathology through TSP-1 signaling. This study will define the role of CD47 signaling in patient biospecimens and mouse models of arthritis, and assess the utility of combinations of anti-CD47 therapy and biologics in RA. Our central hypothesis is that CD47 is critical to RA pathogenesis and that its blockade will ameliorate or reverse inflammatory arthritis and bone erosion. We will test this hypothesis through three specific aims. Aim 1 will characterize the role of the CD47 signaling through TSP-1 and SIRP-a in patients with RA through histologic analysis, single cell RNA sequencing, and synovial organoid cultures. Aim 2 will assess whether CD47 is required for inflammatory arthritis by assessing arthritis, bone outcomes, and cellular function in mice deficient in CD47 after inducing arthritis. Aim 3 will determine the effectiveness of CD47 inhibition in combination with biologic therapies in treating arthritis first using an in vitro drug screen and then testing the most promising candidate therapy in vivo. The proposed research is significant both because it will substantially improve understanding of RA biology, and because it has the potential to identify novel therapeutic strategies which can treat both inflammatory and stromal pathways in RA.