Chemokines in pathogenesis of Experimental Arthritis

实验性关节炎发病机制中的趋化因子

• 批准号: 7906054
• 负责人: SEEMA Singh AHUJA
• 金额: $ 38.02万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-19 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906054
• 关键词: Address; Affect; Affinity; Animal Model; Animals; Antibodies; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Apoptosis; Area; Arthritis; Arts; Autoimmune Process; Autoimmune Responses; Backcrossings; Biological Models; Biology; C-reactive protein; CC chemokine receptor 2; CCL2 gene; Cartilage; Cell physiology; Cells; Characteristics; Chemicals; Chronic; Clinical; Clinical Trials; Collagen; Collagen Arthritis; Communicable Diseases; Complement; Defect; Dendritic Cells; Deposition; Development; Disease; Doctor of Medicine; Employee Strikes; Ensure; Environmental Risk Factor; Event; Experimental Arthritis; Generations; Genetic; Goals; HIV; Human; Hyperplasia; Image; Immune response; Immunity; Immunology; Infection; Inflammation; Inflammatory; Inflammatory Response; Joints; Kinetics; Knock-out; Knockout Mice; Knowledge; Lead; Leukocytes; Ligands; Light; Link; Literature; Maintenance; Mediating; Modeling; Molecular; Molecular Mimicry; Morbidity - disease rate; Mus; Pathogenesis; Patients; Phase; Phase I/II Trial; Phase II Clinical Trials; Phenotype; Play; Population; Positron-Emission Tomography; Process; Publishing; Research; Research Design; Resolution; Rheumatoid Arthritis; Rheumatoid Factor; Role; Staging; Stress; Study Section; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Wild Type Mouse; activity marker; base; beta-Chemokines; bone; cell type; chemokine; chemokine receptor; clinical efficacy; clinically relevant; direct application; expectation; in vivo; innovation; interest; macrophage; member; migration; monocyte; monocyte chemoattractant protein 1 receptor; mortality; neovascularization; novel; programs; receptor; response; stem; therapeutic target; therapy design

DESCRIPTION (provided by applicant): Monocyte chemotactic protien-1 (MCP-1/CCL2) and its high affinity receptor CCR2 play a critical role in leukocyte migration and the generation of inflammatory response. The role of MCP-1/CCR2 axis in resolution of inflammation has not been explored. In three different murine models of arthritis I have shown that genetic inactivation of the CC chemokine receptor (CCR)2 leads to a more severe chronic persistent arthritis. Genetic inactivation of CCR2 results not only in substantial disruptions in Dendritic Cells (DC) and monocyte migration, but also, the CCR2 null state is characterized by the loss of a subtype of DCs implicated in the generation of tolerance. We surmised that because DC and monocytes play critical roles in the different phases of RA and CIA, defects in these cell types occurring as part of the CCR2 null state may greatly contribute to the more severe arthritic phenotype seen in CCR2 KO mice. Thus, in this application we will focus on teasing apart the potential mechanisms by which CCR2 modulates arthritis. To do so we will address the following two Specific Aims : Aim #1 will test the hypothesis that the regulatory role of CCR2 in experimental arthritis is mediated in part via its effects on DCs and/or monocyte macrophage biology. Aim #2 will test the hypothesis that CCR2-dependent cellular processes modulate the kinetics of arthritogenic antibodies deposition and /or clearance. The studies proposed are significant because they will capitalize on our expertise in immunology, chemokine biology and small animal imaging to fill important knowledge gaps in RA pathogenesis, and they are relevant because they address a critical area in chemokine biology with potential therapeutic implications, namely the pathogenic link between CCR2 and RA pathogenesis. The proposed research is innovative because it utilizes state-of-the-art techniques using MicroSPECT, PET and CT imaging for small animals. Rheumatoid Arthritis affects 1% of US population, and therapies designed to block CCR2 are in phase II clinical trials. Thus information obtained from proposed studies which explore how CCR2 modulates arthritis will have significant impact on potential therapeutic strategies to treat this chronic deblitating disease.

描述（由申请人提供）：单核细胞趋化蛋白1（MCP-1/CCL2）及其高亲和力CCR2在白细胞迁移和炎症反应的产生中起关键作用。尚未探索MCP-1/CCR2轴在炎症解决方案中的作用。在三种不同的鼠类关节炎模型中，I已经表明，CC趋化因子受体（CCR）2的遗传失活导致更严重的慢性持续性关节炎。 CCR2的遗传失活不仅导致树突状细胞（DC）和单核细胞迁移的实质性破坏，而且CCR2无效状态的特征是丧失了与耐受性产生有关的DC亚型的丧失。我们推测，由于DC和单核细胞在RA和CIA的不同阶段起关键作用，因此作为CCR2无效状态的这些细胞类型的缺陷可能会极大地促进CCR2 KO小鼠中更严重的关节炎表型。因此，在此应用程序中，我们将重点放在分开CCR2调节关节炎的潜在机制上。为此，我们将解决以下两个具体目标：AIM＃1将检验以下假设：CCR2在实验关节炎中的调节作用部分是通过其对DCS和/或单核细胞巨噬细胞生物学的作用来介导的。 AIM＃2将检验以下假设：CCR2依赖性细胞过程调节关节抗体沉积和 /或清除的动力学。提出的研究之所以重要，是因为它们将利用我们在免疫学，趋化因子生物学和小动物成像方面的专业知识，以填补RA发病机理中重要的知识差距，并且它们具有重要意义，因为它们解决了趋化因子生物学中的关键领域，具有潜在的治疗意义，即CCR2和RA病原体之间的致病联系。拟议的研究具有创新性，因为它利用了小动物的微光谱，PET和CT成像来利用最新技术。类风湿关节炎会影响1％的美国人群，而旨在阻断CCR2的疗法正在II期临床试验中。因此，从提出的研究中获得的信息探讨了CCR2如何调节关节炎将对治疗这种慢性衰减疾病的潜在治疗策略产生重大影响。

项目成果

Critical role of chemokine (C-C motif) receptor 2 (CCR2) in the KKAy + Apoe -/- mouse model of the metabolic syndrome.

• DOI: 10.1007/s00125-011-2248-8
• 发表时间: 2011-10
• 期刊: DIABETOLOGIA
• 影响因子: 8.2
• 作者: Martinez, H. G.;Quinones, M. P.;Jimenez, F.;Estrada, C. A.;Clark, K.;Muscogiuri, G.;Sorice, G.;Musi, N.;Reddick, R. L.;Ahuja, S. S.
• 通讯作者: Ahuja, S. S.

Important role of CCR2 in a murine model of coronary vasculitis.

• DOI: 10.1186/1471-2172-13-56
• 发表时间: 2012-10-17
• 期刊: BMC immunology
• 影响因子: 3
• 作者: Martinez HG;Quinones MP;Jimenez F;Estrada C;Clark KM;Suzuki K;Miura N;Ohno N;Ahuja SK;Ahuja SS
• 通讯作者: Ahuja SS