Understanding A Molecular Cascade That Drives Neutrophil Mediated Pathology In Arthritis

了解驱动中性粒细胞介导的关节炎病理学的分子级联

• 批准号: 10658202
• 负责人: Sanja Arandjelovic
• 金额: $ 49.4万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-09 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658202
• 关键词: Actins; Address; Adhesions; Affect; Alleles; Anti-Bacterial Agents; Arthritis; Attenuated; Bacteria; Biochemical; Biology; CRISPR/Cas technology; Cell Line; Cell surface; Cells; Chronic Disease; Circulation; Collagen; Collagen Arthritis; Communities; Cytoskeleton; Data; Development; Disease; Disease Resistance; Etiology; Event; Exhibits; Genes; Genetic Transcription; HL60; Human; ITGAM gene; Immune; Impairment; Infectious Arthritis; Inflammation; Inflammatory Arthritis; Injections; Integrins; Introns; Joints; K/BxN model; Knowledge; L-Selectin; Leukocytes; Lung; Lymphocyte; Mass Spectrum Analysis; Mediating; Minor; Modeling; Molecular; Molecular Biology; Mus; Neutrophil Activation; Neutrophil Infiltration; Pain; Pathogenicity; Pathology; Patients; Peritoneum; Peritonitis; Phagocytosis; Population; Post-Translational Protein Processing; Proteins; Resolution; Rheumatoid Arthritis; Role; SELL gene; Serum; Signal Transduction; Staphylococcus aureus; Stimulus; Symptoms; Synovial Fluid; Synovial joint; Synovitis; Testing; Therapeutic; Tissues; Transfection; Zymosan; arthropathies; bone; bone erosion; cell motility; cell type; chemokine; chronic pain; diagnostic tool; disorder control; ezrin; improved; in vivo; inhibitor; innovation; microbial; migration; moesin; mouse model; neutrophil; new therapeutic target; novel diagnostics; novel strategies; novel therapeutics; pathogen; peripheral blood; programs; radixin protein; recruit; response; therapeutic development; therapeutic target; tool; transcriptomics

UNDERSTANDING A MOLECULAR CASCADE THAT DRIVES NEUTROPHIL MEDIATED PATHOLOGY IN ARTHRITIS Rheumatoid arthritis (RA) is a frequent chronic disease of the synovial joints characterized by painful loss of mobility due to unrestrained inflammation and progressive bone erosion. Disease etiology is poorly characterized, and the available therapeutic approaches fail to control disease symptoms in many RA patients, highlighting the critical need for identification of new therapeutic targets. A key event in RA is the influx of leukocytes, such as neutrophils, into the joints, where they initiate and sustain inflammation and contribute to bone erosion from the early stages of RA. While healthy synovial fluid is acellular, the most abundant cell type found in the inflamed synovial fluid is the activated neutrophil. Engulfment and cell motility protein-1 (ELMO1) is a regulator of actin cytoskeleton dynamics during phagocytosis of dying cells and migration of lymphocytes. We demonstrated that Elmo1–/– mice develop significantly milder disease in two models of inflammatory arthritis that share many features with human RA, and that deletion of Elmo1 during established disease could improve arthritis symptoms and disease resolution. We found that disease resistance is due to specific ELMO1 function in neutrophils, and that loss of ELMO1 significantly attenuated neutrophil activation and migration (induced by chemokines involved in arthritis) and reduced neutrophil mobilization to the joints. Circulating Elmo1–/– neutrophils had reduced cell surface levels of the tethering molecule CD62L, and reduced chemokine-induced exposure of the adhesion/migration-promoting integrin CD11b. These data suggest that ELMO1 function may be required for multiple steps of the neutrophil recruitment cascade to enhance neutrophil recruitment into joints. Surprisingly, loss of ELMO1 did not impair neutrophil recruitment and function elicited by bacterial stimuli, indicating that therapeutic targeting of ELMO1 could maintain normal pathogen clearance. Finally, the RA-associated SNP rs11984075, located in an intron of the ELMO1 gene, correlates with increased ELMO1 protein and elevated CD62L in neutrophils, suggesting that RA patients with SNP rs11984075 could benefit from therapeutic approaches targeting ELMO1. We hypothesize that ELMO1 contributes to tissue/stimulus-specific neutrophil recruitment and pathology in inflammatory arthritis. In this proposal, we will address three specific aims: 1. Test if ELMO1 is required for stimulus- or tissue- specific neutrophil recruitment. 2. Test if ELMO1 promotes neutrophil adhesion through CD62L/L-selectin, and 3. Identify the mechanism by which ELMO1 SNP rs11984075 elevates protein levels and test an inhibitor of ELMO1 in arthritis. This proposal is significant because it will further our understanding of the role of ELMO1 in neutrophil-mediated pathology in rheumatoid arthritis and could lead to the discovery of new diagnostic tools and therapeutic strategies. Our proposal is innovative because it will advance new concepts in ELMO1 biology and will generate new tools for the scientific community and for studying neutrophil functions.

了解驱动关节炎中嗜中性粒细胞病理学的分子级联 类风湿关节炎（RA）是滑膜关节的慢性疾病，其特征是疼痛丧失 由于炎症和进行性骨骼侵蚀而引起的活动能力。疾病病因很差 表征，可用的治疗方法无法控制许多RA患者的疾病症状， 强调确定新治疗靶标的批判性需求。 RA中的关键事件是 白细胞（例如中性粒细胞）进入关节，在那里它们启动和维持注射，并有助于 RA早期阶段的骨侵蚀。虽然健康的滑液是细胞的，但最丰富的细胞类型 在发炎的滑液中发现的是活化的中性粒细胞。 吞噬和细胞运动蛋白1（ELMO1）是肌动蛋白细胞骨架动力学的调节剂 垂死细胞的吞噬作用和淋巴细胞的迁移。我们证明了Elmo1 - / - 小鼠的发展 在两种模型的炎症性关节炎模型中，米勒病很明显，与人类RA具有许多特征， 在既定疾病期间删除ELMO1可以改善关节炎症状和疾病的缓解。我们 发现抗病性是由于中性粒细胞中特定的ELMO1功能引起的，并且Elmo1的丧失 显着减弱中性粒细胞的激活和迁移（由关节炎涉及的趋化因子诱导）和 中性粒细胞动员减少到关节。循环ELMO1 - / - 中性粒细胞降低了细胞表面水平 绑定分子CD62L，并减少了趋化因子诱导的粘附/迁移促进的暴露 整合素CD11b。这些数据表明，中性粒细胞的多个步骤可能需要ELMO1功能 招募级联以将中性粒细胞招募成关节。令人惊讶的是，Elmo1的损失没有损害 细菌刺激引起的中性粒细胞募集和功能，表明ELMO1的治疗性靶向 可以维持正常的病原体清除率。最后，与RA相关的SNP RS11984075，位于 ELMO1基因与中性粒细胞中Elmo1蛋白增加并升高CD62L相关，表明 SNP RS11984075的RA患者可以通过针对ELMO1的治疗方法受益。我们假设 ELMO1有助于组织/刺激特异性嗜中性粒细胞募集和炎症性关节炎病理学。 在此提案中，我们将解决三个具体目标：1。测试是否需要ELMO1进行刺激或组织 - 特定的中性粒细胞募集。 2。测试ELMO1是否通过CD62L/L-选择素促进中性粒细胞粘合剂，并且 3。确定ELMO1 SNP RS11984075升高蛋白质水平并测试抑制剂的机制 ELMO1关节炎。该提议很重要，因为它将进一步了解Elmo1在 类风湿关节炎中嗜中性粒细胞介导的病理学，可能导致发现新的诊断工具和 治疗策略。我们的建议具有创新性，因为它将推进Elmo1生物学的新概念和 将为科学界和研究中性粒细胞功能生成新的工具。