Immune Regulation by Gadd45b and Gadd45g

描述（由申请人提供）：我们的长期目标是了解控制自身免疫性疾病的分子机制。我们目前的重点是一个名为Gadd 45（生长停滞和DNA损伤诱导）的基因家族，它由三个成员组成，Gadd 45 a，Gadd 45 b和Gadd 45 g。Gadd 45 a被证明参与调节T细胞的稳态，并且已知缺乏Gadd 45 a会导致狼疮。另外两个家族成员Gadd 45 b和Gadd 45 g在自身免疫性疾病中的作用尚不清楚。在Th 1细胞中，Gadd 45 b和Gadd 45 g，而不是Gadd 45 a，由TCP信号或IL-12和IL-18诱导。我们已经发现，缺乏Gadd 45 b和Gadd 45 g导致针对单核细胞增生李斯特菌的Th 1细胞数量急剧减少。预期Th 1细胞数量减少，我们惊讶地看到Gadd 45 b缺失导致实验性过敏性脑脊髓炎（EAE）加重，临床症状更严重，病程延长，炎症CNS中自身反应性Th 1细胞增加。Gadd 45 b缺失也导致老年小鼠脾脏肿大。Gadd 45 b/Gadd 45 g双缺陷进一步加重了这种表型，并导致老年小鼠的脾脏比Gadd 45 b单缺失小鼠大大增大。脾脏增大是由于具有活化表型的CD 4 + T细胞和B细胞的积累。我们的数据表明，Gadd 45 b和Gadd 45 g在调节活化的CD 4 + T细胞中发挥协同作用。此外，我们发现Gadd 45 b和Gadd 45 g抑制活化的CD 4 + T细胞的增殖，并且是活化的CD 4 + T细胞凋亡所必需的。在这项提案中，我们正在测试的假设，Gadd 45蛋白家族成员Gadd 45 b和Gadd 45 g是重要的自身免疫性负调节。具体来说，我们计划：1。提供明确的证据表明Gadd 45 b和Gadd 45 g协同调节自身免疫性疾病，2.确定Gadd 45 b和Gadd 45 g是否对于控制EAE中的T细胞增殖和凋亡至关重要，以及3.研究Gadd 45 b和Gadd 45 g调节Th 1细胞增殖和凋亡的分子机制。Gadd 45家族分子对外周效应性CD 4 + T细胞增殖和凋亡的调控为自身免疫提供了新的调控机制。相关性：这项研究将导致针对这些分子的新策略的发展，以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。

DESCRIPTION (provided by applicant): 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.