Transcriptional Checkpoints Of Autoimmune Encephalomyelitis

这项研究计划的总体目标是阐明一种新的病理机制 潜在的自身免疫性疾病，如多发性硬化症（MS），并测试一类新的 该提案的灵感来自最近的两条线， 发现：（i）在人类中，几项独立建立的全基因组关联研究 c-Rel是Rel/核因子-kB（Rel/NF-kB）家族的淋巴样和髓样成员， 包括MS在内的六种自身免疫性疾病的风险因素;（ii）在小鼠中，c-Rel缺乏使它们 对自身免疫性脑脊髓炎、关节炎和结肠炎具有抗性， 感染.因此，我们推测c-Rel既是一个危险因素，也是一个致病因素， 人类自身免疫性疾病和针对它的药物应该是有效的治疗， 疾病为了测试这一理论，我们开发了一类新的小分子，专门 通过阻止其与DNA结合来抑制c-Rel功能。在小鼠中，这些化合物高度 有效抑制自身免疫反应和改善正在进行的实验性 自身免疫性脑脊髓炎，多发性硬化症的动物模型。该建议的具体目标是 阐明c-Rel控制自身免疫性脑脊髓炎的机制， 为了验证这一理论，即抑制炎症性和调节性T细胞中的c-Rel是必要的， 治愈自身免疫性脑脊髓炎具体来说，我们将测试的假设，（i）c-Rel服务 作为自身免疫性脑脊髓炎的转录检查点;（ii）c-Rel控制自身免疫性脑脊髓炎 脑脊髓炎的细胞和基因特异性的方式;和（iii）c-Rel阻断减少抗- 多发性硬化症患者的髓鞘免疫反应。

The overall objective of this research proposal is to elucidate a new pathological mechanism underlying autoimmune diseases such as multiple sclerosis (MS) and to test a new class of therapeutic compounds in models of MS. The proposal is inspired by two lines of recent discoveries: (i) in humans, several genome-wide association studies independently established that c-Rel, the lymphoid and myeloid member of the Rel/nuclear factor-kB (Rel/NF-kB) family, is a risk factor for six autoimmune diseases including MS; (ii) in mice, c-Rel deficiency renders them resistant to autoimmune encephalomyelitis, arthritis, and colitis while having limited impact on infections. We therefore theorized that c-Rel is both a risk factor and a pathogenic factor for human autoimmune diseases and that drugs targeting it should be effective for treating the diseases. To test this theory, we have developed a new class of small molecules that specifically inhibits c-Rel function by preventing its binding to DNA. In mice, these compounds are highly effective in suppressing autoimmune responses and in ameliorating ongoing experimental autoimmune encephalomyelitis, an animal model for MS. The specific goals of this proposal are to elucidate the mechanism(s) through which c-Rel controls autoimmune encephalomyelitis, and to test the theory that inhibition of c-Rel in both inflammatory and regulatory T cells is required to cure autoimmune encephalomyelitis. Specifically, we will test the hypotheses that (i) c-Rel serves as a transcriptional checkpoint of autoimmune encephalomyelitis; (ii) c-Rel controls autoimmune encephalomyelitis in a cell- and gene-specific manner; and (iii) c-Rel blockade diminishes anti- myelin immune responses of multiple sclerosis patients.