Role of the CD47 Pathway in Rheumatoid Arthritis Pathogenesis and Treatment

项目摘要 类风湿性关节炎(RA)代表一个慢性进行性过程，导致显著的 发病率和死亡率。RA是由炎症和间质病理共同驱动的，虽然 目前的治疗方法可以改善炎症，但还没有针对成纤维细胞的有效治疗方法 类风湿关节炎患者的骨组织病理改变。CD47途径可以影响免疫细胞的吞噬作用 通过SIRP-a信号转导，通过TSP-1信号转导间质病理。这项研究将界定 CD47信号在患者生物标本和小鼠关节炎模型中的作用，并评估 联合抗CD47治疗和生物制剂在类风湿关节炎中的应用。我们的中心假设是 CD47在类风湿关节炎的发病机制中起关键作用，其阻断将改善或逆转 炎症性关节炎和骨质侵蚀。我们将通过三个具体的例子来检验这一假设 目标。目标1将描述CD47信号通过TSP-1和SIRP-a在 对类风湿关节炎患者进行组织学分析、单细胞RNA测序和滑膜组织学检查 文化。AIM 2将通过评估CD47是否是炎症性关节炎所必需的 诱导关节炎后CD47缺陷小鼠的关节炎、骨转归和细胞功能。 目标3将确定CD47抑制与生物治疗相结合的有效性 在治疗关节炎方面，首先使用体外药物筛选，然后测试最有希望的 体内候选治疗。这项拟议的研究具有重要意义，因为它将在很大程度上 提高对类风湿关节炎生物学的理解，因为它有可能识别新的 可以同时治疗类风湿关节炎炎症和间质通路的治疗策略。

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.