Development of a Novel RA/Atherosclerosis Mouse Model

描述(申请人提供)：患有类风湿性关节炎(RA)的人类表现出更大的动脉粥样硬化负担，导致死亡率增加。由于缺乏合适的动物模型，人们对这种关系的理解一直受到阻碍。我们发现，K/BxAg7小鼠在4-5周龄时开始出现自发性关节炎，然后在接受致动脉粥样硬化的饮食时出现严重的动脉粥样硬化。因此，我们第一次引入了一种可以忠实地概括这两种人类疾病的小鼠模型。该项目将利用K/BxAg7小鼠来确定导致关节炎小鼠动脉粥样硬化发展的关键细胞机制。我们将重点关注巨噬细胞，因为它们在这两种疾病的发病机制中都是至关重要的。使用CD11b-白喉毒素受体结构特异性地耗尽巨噬细胞的采用转移模型将被用于测试巨噬细胞是否在关节炎和动脉粥样硬化的发展中是必需的。预计吞噬巨噬细胞将缓解这两种疾病。单核细胞进入组织后的命运将使用绿色荧光蛋白报告鼠进行跟踪。预计组织中巨噬细胞的聚集将平行于疾病的进展。通过Luminex分析和流式细胞仪检测，我们预计K/BxAg7小鼠的血清、关节和动脉粥样硬化病变将表达更高水平的炎性细胞因子和趋化因子。最后，我们将测试已建立的(肿瘤坏死因子和白介素6受体拮抗剂和他汀类药物)疗法对K/BxAg7动物关节炎和动脉粥样硬化发展的影响。我们预测，这两种疾病的改善将与组织巨噬细胞的减少相关。

DESCRIPTION (provided by applicant): Humans with rheumatoid arthritis (RA) demonstrate greater atherosclerotic burden, leading to increased mortality. Progress in understanding this relationship has been hampered by the lack of a suitable animal model. We found that K/BxAg7 mice develop spontaneous arthritis beginning at 4-5 weeks of age followed by severe aortic atherosclerosis when receiving an atherogenic diet. Thus, for the first time, we introduce a mouse model that faithfully recapitulates both human diseases. This project will utilize K/BxAg7 mice to identify the key cellular mechanisms responsible for the development of atherosclerosis in arthritic mice. We will focus on macrophages, as they are crucial for the pathogenesis of both diseases. An adoptive transfer model in which macrophages are specifically depleted using a CD11b-diphtheria toxin receptor construct will be used to test whether macrophages are required for the development of arthritis and atherosclerosis. It is expected that depletion of macrophages will mitigate both diseases. Monocyte fate as they enter tissues will be tracked using Green Fluorescent Protein reporter mice. It is expected that tissue macrophage accumulation will parallel disease progression. We anticipate that serum, joints, and atherosclerotic lesions from K/BxAg7 mice will express increased levels of inflammatory cytokines and chemokines as measured by luminex assays and flow cytometry. Lastly, we will test the effects of established (TNF and IL-6 receptor antagonists and statins) therapies on the development of arthritis and atherosclerosis in K/BxAg7 animals. We predict that amelioration of both diseases will correlate with a reduction in tissue macrophages.