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 多发性硬化症模型中的治疗化合物该提议的灵感来自于最近的两行 发现：(I)在人类身上，独立建立的几项全基因组关联研究 C-Rel是Rel/核因子-kB(Rel/NF-kB)家族的淋巴和髓系成员，是 包括多发性硬化症在内的六种自身免疫性疾病的危险因素；(Ii)在小鼠中，c-Rel缺乏使它们 抵抗自身免疫性脑脊髓炎、关节炎和结肠炎，但对 感染。因此，我们推测c-rel既是一种危险因素，也是一种致病因素。 人类自身免疫性疾病和针对它的药物应该有效地治疗 疾病。为了测试这一理论，我们开发了一类新的小分子，特别是 通过阻止c-rel与DNA结合来抑制其功能。在老鼠身上，这些化合物的含量很高 有效抑制自身免疫反应和改善正在进行的实验 自身免疫性脑脊髓炎，一种MS的动物模型。这项提议的具体目标是 阐明c-Rel抑制自身免疫性脑脊髓炎的机制(S)，以及 为了验证炎症和调节性T细胞都需要抑制c-rel的理论 治愈自身免疫性脑脊髓炎。具体地说，我们将测试(I)c-rel服务的假设 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 细胞和基因特异性的脑脊髓炎；和(Iii)c-Rel的阻断降低了抗- 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.