Development of a Novel RA/Atherosclerosis Mouse Model

描述（由申请人提供）：类风湿性关节炎（RA）患者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，理解这种关系的进展受到阻碍。我们发现，K/BxAg 7小鼠在4-5周龄时开始发生自发性关节炎，随后在接受致动脉粥样硬化饮食时发生严重的主动脉粥样硬化。因此，我们第一次引入了一种忠实地再现这两种人类疾病的小鼠模型。该项目将利用K/BxAg 7小鼠来确定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，因为它们对这两种疾病的发病机制至关重要。将使用CD 11b-白喉毒素受体构建体特异性耗竭巨噬细胞的过继转移模型来测试巨噬细胞是否是关节炎和动脉粥样硬化发展所必需的。预计巨噬细胞的耗竭将减轻这两种疾病。将使用绿色荧光蛋白报告小鼠跟踪单核细胞进入组织时的命运。预计组织巨噬细胞蓄积将与疾病进展平行。我们预期，K/BxAg 7小鼠的血清、关节和动脉粥样硬化病变将表达增加水平的炎性细胞因子和趋化因子，如通过Luminex测定和流式细胞术测量的。最后，我们将测试已建立的（TNF和IL-6受体拮抗剂和他汀类药物）治疗对K/BxAg 7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.