Immune Regulation by Gadd45b and Gadd45g

Gadd45b 和 Gadd45g 的免疫调节

• 批准号: 7031286
• 负责人: Binfeng Lu
• 金额: $ 31.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031286
• 关键词: apoptosis

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.

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。我们当前关注的焦点是一个名为 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 被证明参与调节 T 细胞的稳态，已知缺乏 Gadd45a 会导致狼疮。另外两个家族成员 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（而非 Gadd45a）由 TCP 信号传导或 IL-12 和 IL-18 诱导。我们发现，Gadd45b 和 Gadd45g 的缺乏会导致针对单核细胞增生李斯特氏菌的 Th1 细胞数量急剧减少。我们预计 Th1 细胞数量较低，但惊讶地发现 Gadd45b 缺失导致实验性过敏性脑脊髓炎 (EAE) 恶化，临床症状更严重，病程延长，发炎中枢神经系统中自身反应性 Th1 细胞增加。 Gadd45b 缺失还会导致老年小鼠的脾脏增大。与 Gadd45b 单缺失相比，Gadd45b/Gadd45g 双缺陷进一步加剧了这种表​​型，并导致老年小鼠的脾脏大大增大。脾脏增大是由于具有激活表型的 CD4+ T 细胞和 B 细胞的积累所致。我们的数据表明 Gadd45b 和 Gadd45g 在调节活化的 CD4+ T 细胞中发挥协同作用。此外，我们发现 Gadd45b 和 Gadd45g 抑制增殖，并且是激活的 CD4+ T 细胞凋亡所必需的。在本提案中，我们正在测试以下假设：Gadd45 蛋白家族成员 Gadd45b 和 Gadd45g 是自身免疫的重要负调节因子。具体来说，我们计划：1.提供Gadd45b和Gadd45g协调调节自身免疫性疾病的明确证据，2.确定Gadd45b和Gadd45g是否对于控制EAE中的T细胞增殖和凋亡至关重要，以及3.研究调节增殖的分子机制Gadd45b 和 Gadd45g 对 Th1 细胞的凋亡作用。 Gadd45分子家族对外周效应CD4+ T细胞增殖和凋亡的调节为自身免疫提供了新的调节机制。相关性：这项研究将导致针对这些分子的新策略的开发，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。