Role of the CD47 Pathway in Rheumatoid Arthritis Pathogenesis and Treatment

CD47 通路在类风湿关节炎发病机制和治疗中的作用

基本信息

批准号：
10707155
负责人：
Benjamin Douglas Korman
金额：
$ 51.52万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2022-09-20 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707155
关键词：
3-Dimensional Acceleration Address Affect American Anti-CD47 Arthritis Binding Biological Products Biological Response Modifier Therapy Biology CD47 gene Cell physiology Cells Chronic Clinical Clinical assessments Collagen Arthritis Combined Modality Therapy DNA Sequence Alteration Data Degenerative polyarthritis Disease Disease remission Drug Screening Eating Fibroblasts Fibrosis Gene Expression Genomics Goals Histologic Histology Homeostasis Immune In Vitro Inflammation Inflammatory Inflammatory Arthritis Ligands Macrophage Malignant Neoplasms Membrane Proteins Mesenchymal Modeling Morbidity - disease rate Mus Myeloid Cells Organoids Osteoclasts Outcome PTPNS1 gene Pain Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phagocytosis Phenotype Process Production Proliferating Proteins Refractory Research Rheumatoid Arthritis Role Signal Transduction Source Synovial Membrane Synovitis T-Lymphocyte TNF gene Testing Therapeutic Work antigen processing arthritis therapy bone bone erosion bone loss chronic autoimmune disease clinical remission cytokine disability effectiveness evaluation improved in vivo innovation insight joint destruction migration monocyte mortality mouse model novel therapeutic intervention overexpression prevent radiological imaging receptor single cell analysis single-cell RNA sequencing symptomatic improvement transcriptome sequencing treatment strategy

项目摘要

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.

项目概要类风湿性关节炎 (RA) 是一种慢性进展过程，会导致严重的发病率和死亡率。 RA 是由炎症和间质病理共同驱动的，同时目前的疗法可以改善炎症，但没有针对成纤维细胞的有效治疗方法和 RA 的骨病理学。 CD47通路可以影响免疫细胞的吞噬作用通过 SIRP-a 信号传导和基质病理学通过 TSP-1 信号传导。这项研究将定义 CD47 信号传导在患者生物样本和关节炎小鼠模型中的作用，并评估抗 CD47 疗法和生物制剂联合治疗 RA 的效用。我们的中心假设是 CD47 对 RA 发病机制至关重要，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测试来检验这个假设目标。目标 1 将描述 CD47 信号通过 TSP-1 和 SIRP-a 在通过组织学分析、单细胞 RNA 测序和滑膜类器官对 RA 患者进行分析文化。目标 2 将通过评估 CD47 是否是炎性关节炎所必需的诱导关节炎后缺乏 CD47 的小鼠的关节炎、骨骼结果和细胞功能。目标 3 将确定 CD47 抑制与生物疗法相结合的有效性首先使用体外药物筛选来治疗关节炎，然后测试最有希望的药物体内候选疗法。拟议的研究意义重大，因为它将极大地提高对 RA 生物学的理解，并且因为它有潜力识别新的可以治疗 RA 炎症和基质途径的治疗策略。