IL-1R1, MMP-9, and EAE

项目总结 多发性硬化症(MS)是一种重要的神经系统疾病，在美国影响着数百万人。 这种疾病被认为是由针对脑内髓鞘的自身免疫活动引起的 中枢神经系统。实验性自身免疫性脑脊髓炎复制多发性硬化症模型 (EAE)，它模仿了MS的许多方面，白介素1(IL-1)信号已被证明是 在EAE的发病机制中是必不可少的，但由哪种细胞类型特异性IL-1受体介导 目前尚不清楚EAE所需的流程。此外，基质金属蛋白酶9(MMP9)是 已知在EAE期间在调节血脑屏障的破坏中发挥重要作用。 我们的初步结果显示，内皮细胞IL-1受体1(eIL-1R1)和T细胞IL-1受体 1型(TCIL-1R1)可能都是介导EAE发病机制的不同方面所必需的， IL-1R1和MMP9在EAE过程中可能相互放大作用。此应用程序是 旨在：1)演示eIL-1R1和TCIL-1R1结合在一起介导EAE的诱导；2)识别 基质金属蛋白酶-9在eIL-1R1和TCIL-1R1介导的自身免疫过程中的作用；3)确定 IL-1R1和MMP9特异性抑制剂是否协同阻断EAE的诱导和进展。

PROJECT SUMMARY Multiple sclerosis (MS) is a significant neurological disease affecting millions of people in the US. This disease is believed to be driven by autoimmune activities against the myelin sheath in the central nervous system. MS is modeled by the experimental autoimmune encephalomyelitis (EAE), which mimics many aspects of MS. Interleukin-1 (IL-1) signaling has been shown to be essential for the pathogenesis of EAE, but which cell-type specific IL-1 receptor mediated processes are required for EAE are unclear. In addition, matrix metalloproteinase 9 (MMP-9) is known to play an important role in mediating the breakdown of the blood brain barrier during EAE. Our preliminary results show endothelial IL-1 receptor type 1 (eIL-1R1) and T cell IL-1 receptor type 1 (TcIL-1R1) may both be required to mediate different aspects of the EAE pathogenesis, and IL-1R1 and MMP-9 may amplify each other’s function during EAE. This application is designed to: 1) Demonstrate eIL-1R1 and TcIL-1R1 combine to mediate EAE induction; 2) Identify the roles of MMP-9 in eIL-1R1 and TcIL-1R1 mediated autoimmune processes; and 3) Determine whether IL-1R1 and MMP-9 specific inhibitors synergistically block EAE induction and progression.