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.

理解驱动关节炎中性粒细胞介导病理的分子级联 类风湿性关节炎（RA）是一种常见的慢性滑膜关节疾病，以疼痛性关节炎为特征 由于无限制的炎症和进行性骨质侵蚀导致的活动能力下降。疾病病因学不佳 特征，并且可用的治疗方法不能控制许多RA患者的疾病症状， 突出了鉴定新的治疗靶点的迫切需要。RA的一个关键事件是 白细胞，如中性粒细胞，进入关节，在那里它们引发和维持炎症，并有助于 早期类风湿关节炎的骨质侵蚀而健康的滑液是无细胞的，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（ELMO 1）是细胞生长过程中肌动蛋白细胞骨架动力学的调节因子。 死亡细胞的吞噬作用和淋巴细胞的迁移。我们证明了Elmo 1-/-小鼠 在与人类RA共享许多特征的两种炎性关节炎模型中， 在已建立的疾病期间删除Elmo 1可以改善关节炎症状和疾病消退。我们 发现疾病抵抗力是由于中性粒细胞中特异性ELMO 1功能，ELMO 1的丧失 显著减弱中性粒细胞活化和迁移（由关节炎相关趋化因子诱导）， 减少中性粒细胞向关节的动员。循环Elmo 1-/-中性粒细胞具有降低的细胞表面水平， 栓系分子CD 62 L，并减少趋化因子诱导的粘附/迁移促进因子的暴露。 整合素CD 11b。这些数据表明，ELMO 1功能可能需要多个步骤的中性粒细胞 募集级联，以增强中性粒细胞募集到关节中。令人惊讶的是，ELMO 1的缺失并没有损害 由细菌刺激引起的中性粒细胞募集和功能，表明ELMO 1的治疗靶向 可以维持正常的病原体清除最后，RA相关SNP rs 11984075位于 ELMO 1基因与中性粒细胞中ELMO 1蛋白增加和CD 62 L升高相关，表明 具有SNP rs 11984075的RA患者可以从靶向ELMO 1的治疗方法中获益。我们假设 ELMO 1有助于组织/刺激特异性中性粒细胞募集和炎症性关节炎的病理学。 在这一建议中，我们将解决三个具体目标：1。测试是否需要ELMO 1用于刺激或组织- 特异性中性粒细胞募集。2.测试ELMO 1是否通过CD 62 L/L-选择素促进中性粒细胞粘附，以及 3.确定ELMO 1 SNP rs 11984075升高蛋白质水平的机制，并测试ELMO 1 SNP rs 11984075的抑制剂。 ELMO 1在关节炎中的作用这一建议意义重大，因为它将进一步加深我们对ELMO 1在以下方面的作用的理解： 在类风湿性关节炎中的嗜中性粒细胞介导的病理学，并可能导致新的诊断工具的发现， 治疗策略我们的建议是创新的，因为它将推进ELMO 1生物学的新概念， 将为科学界和研究中性粒细胞功能提供新的工具。