IL-1R1, MMP-9, and EAE

项目摘要 多发性硬化症（MS）是一种重要的神经系统疾病，影响着美国数百万人。 这种疾病被认为是由针对髓鞘的自身免疫活动驱动的。 中枢神经系统MS是由实验性自身免疫性脑脊髓炎 (EAE)白细胞介素-1（IL-1）信号转导已被证明是MS的一个重要组成部分。 EAE的发病机制是必需的，但其中细胞类型特异性IL-1受体介导 EAE所需的流程尚不清楚。此外，基质金属蛋白酶9（MMP-9）是 已知在EAE期间介导血脑屏障的破坏中起重要作用。 我们的初步结果表明，内皮细胞IL-1受体1（eIL-1 R1）和T细胞IL-1受体 1型（TcIL-1 R1）可能都需要介导EAE发病机制的不同方面， IL-1 R1和MMP-9在EAE中可能相互放大作用。本申请是 旨在：1）证明eIL-1 R1和TcIL-1 R1联合收割机介导EAE诱导; 2）鉴定 MMP-9在eIL-1 R1和TcIL-1 R1介导的自身免疫过程中的作用;以及3）确定 IL-1 R1和MMP-9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.