Immune Regulation by Gadd45b and Gadd45g

Gadd45b 和 Gadd45g 的免疫调节

• 批准号: 7746479
• 负责人: Binfeng Lu
• 金额: $ 29.86万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746479
• 关键词: Affect; Apoptosis; Apoptotic; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; CD4 Positive T Lymphocytes; Cells; Clinical; Complex; Data; Development; Disease; Disease Marker; Effector Cell; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Family; Family member; Flow Cytometry; G2/M Transition; GADD45; GADD45A gene; GADD45B; GADD45B/GADD45G; GADD45G; Gene Family; Genes; Growth; Histocytochemistry; Homeostasis; Immune; Infection; Interleukin-10; Interleukin-12; Interleukin-18; Kinetics; Lead; Listeria monocytogenes; Lupus; Lymphoid Tissue; MAPK14 gene; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Multiple Sclerosis; Mus; Peripheral; Phenotype; Play; Protein Family; Regulation; Role; Signal Transduction; Spleen; Splenomegaly; T-Cell Proliferation; T-Lymphocyte; Testing; Th1 Cells; Transgenic Organisms; Wild Type Mouse; insight; member; mitogen-activated protein kinase p38; mouse model; novel strategies; prevent; response

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.

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 目前的焦点是一个名为Gadd 45（生长停滞和DNA损伤诱导）的基因家族， 由三个成员组成，Gadd 45 a、Gadd 45 b和Gadd 45 g。Gadd 45 a被证明参与了 已知调节T细胞的体内平衡和缺乏Gadd 45 a会引起狼疮。另外两个的作用 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。我们发现，缺乏 Gadd 45 b和Gadd 45 g导致针对单核细胞增多性李斯特菌的Th 1细胞数量急剧减少。 预期Th 1细胞数量较少，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，临床体征更严重， 病程和增加的自身反应性Th 1细胞在发炎的中枢神经系统。Gadd 45 b缺失也导致了 老年小鼠的脾脏肿大。Gadd 45 b/Gadd 45 g双缺陷进一步加重了这种表型， 与Gadd 45 b单一缺失相比，在老年小鼠中导致脾脏大大增大。的扩大 脾脏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 提示Gadd 45 b和Gadd 45 g在调节活化CD 4 + T细胞中发挥协同作用。此外，本发明还提供了一种方法， 我们发现Gadd 45 b和Gadd 45 g抑制增殖，并且是活化的细胞凋亡所必需的。 CD 4 + T淋巴细胞。在这项提议中，我们正在测试Gadd 45蛋白家族成员Gadd 45 b 和Gadd 45 g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 证明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在EAE中对T细胞增殖和凋亡的调控起关键作用。研究分子 Gadd 45 b和Gadd 45 g调控Th 1细胞增殖和凋亡的机制。调控 Gadd 45家族分子对外周效应CD 4 + T细胞增殖和凋亡的影响提供了一种新的研究方法。 自身免疫的新调节机制。 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。