Immune Regulation by Gadd45b and Gadd45g

我们的长期目标是了解控制自身免疫性疾病的分子机制。我们的 目前的焦点是一个名为GADD45(生长停滞和DNA损伤诱导)的基因家族，它 由三个成员组成，Gadd45a、Gadd45b和Gadd45g。Gadd45a被证明参与了 调节T细胞的动态平衡和缺乏Gadd45a被认为是导致狼疮的原因。另外两个人的角色 家族成员Gadd45b和Gadd45g在自身免疫性疾病中的作用尚不清楚。在Th1细胞中，Gadd45b和 Gadd45g，而不是Gadd45a，是由TCP信号或IL-12和IL-18诱导的。我们发现，缺乏 Gadd45b和Gadd45g导致抗单核细胞增多性李斯特菌的Th1细胞数量急剧减少。 预计Th1细胞数量较少，但我们惊讶地看到Gadd45b缺失导致 加重实验性变态反应性脑脊髓炎(EAE)，临床症状更严重，延长 炎症的中枢神经系统中的病程和自身反应性Th1细胞的增加。Gadd45b的缺失也导致了 老年小鼠的脾增大。Gadd45B/Gadd45G双缺乏进一步加剧了这种表型和 导致与Gadd45b单缺失相比，老年小鼠的脾大大增大。的扩大。 脾是由于活化表型的CD4T细胞和B细胞的聚集所致。我们的数据 提示Gadd45b和Gadd45g在调节活化的CD4T细胞中起协同作用。此外, 我们发现Gadd45b和Gadd45g抑制了细胞的增殖，并且是激活的细胞凋亡所必需的 CD4T细胞。在这个提议中，我们检验了GADD45蛋白家族成员Gadd45b的假设 和Gadd45G是自身免疫的重要负性调节因子。具体来说，我们计划：1.提供明确的 证明Gadd45b和Gadd45g协调调节自身免疫性疾病，2.确定Gadd45b和Gadd45g是否 Gadd45G在控制EAE中T细胞增殖和凋亡中起关键作用；3.分子研究 Gadd45b和Gadd45G调节Th1细胞增殖和凋亡的机制监管 GADD45家族分子对外周效应CD4T细胞增殖和凋亡的影响 新的自身免疫调控机制。 相关性：这项研究将导致开发针对这些分子的新策略来治疗或 预防自身免疫性疾病。这项研究还将揭示自身免疫性疾病的新疾病标志物。

Our long term objective is to understand the molecular mechanisms that control autoimmune diseases. Our immediate focus is on a gene family called Gadd45 (growth-arrest and DNA damage-inducible) which consists of three members,Gadd45a, Gadd45b, and Gadd45g. Gadd45a was shown to be involved in regulating homeostasis of T cells and lack of Gadd45a was known to cause lupus. The role of the other two family members, Gadd45b and Gadd45g, in autoimmune diseases is not clear. In Th1 cells, Gadd45b and Gadd45g, but not Gadd45a, are induced by TCP signaling or IL-12 and IL-18. We have found that the lack of Gadd45b and Gadd45g results in a drastically reduced number of Th1 cells against Listeria monocytogenes. Expecting low numbers of Th1 cells, we were surprised to see that Gadd45b deletion resulted in exacerbated experimental allergic encephalomyelitis (EAE) with more severe clinical signs, a prolonged disease course and increased autoreactive Th1 cells in the inflamed CNS. Gadd45b deletion also resulted in enlarged spleens in older mice. Gadd45b/Gadd45g double-deficiency further aggravated this phenotype and resulted in greatly enlarged spleens in older mice compared to Gadd45b single deletion. The enlargement of spleens was due to the accumulation of CD4+ T cells with an activated phenotype and B cells. Our data suggest that Gadd45b and Gadd45g play a synergistic role in regulating activated CD4+ T cells. In addition, we found that Gadd45b and Gadd45g inhibited proliferation and were required for apoptosis of activated CD4+ T cells. In this proposal we are testing the hypothesis that Gadd45 protein family members Gadd45b and Gadd45g are important negative regulators of autoimmunity. Specifically we plan to: 1. provide definitive proof that Gadd45b and Gadd45g coordinately regulate autoimmune diseases, 2. determine if Gadd45b and Gadd45g are critical for the control of T cell proliferation and apoptosis in EAE, and 3. study molecular mechanisms that regulate the proliferation and apoptosis of Th1 cells by Gadd45b and Gadd45g. Regulation of proliferation and apoptosis in peripheral effector CD4+ T cells by Gadd45 family of molecules provides a new regulatory mechanism for autoimmunity. Relevance: This study will lead to the development of novel strategies targeting these molecules to treat or prevent autoimmune diseases. This study will also reveal new disease markers for autoimmune diseases.