Immune Regulation by Gadd45b and Gadd45g

Gadd45b 和 Gadd45g 的免疫调节

• 批准号: 7330322
• 负责人: Binfeng Lu
• 金额: $ 30.16万
• 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/7330322
• 关键词: Affect; Apoptosis; Apoptotic; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; CD4 Positive T Lymphocytes; Cells; Clinical; Complex; DNA Damage; Data; Development; Disease; Disease Marker; Effector Cell; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Family; Family member; Flow Cytometry; G2/M Transition; 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; Numbers; Peripheral; Phenotype; Play; Protein Family; Regulation; Role; Signal Transduction; Spleen; Splenomegaly; T-Cell Proliferation; T-Lymphocyte; Testing; Th1 Cells; Transgenic Organisms; Wild Type Mouse; human MAPK14 protein; 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。我们的 直接的重点是一个名为GADD45的基因家族（生长骚扰和DNA损伤诱导），该家族 由三名成员，GADD45A，GADD45B和GADD45G组成。 GADD45A被证明参与了 已知调节T细胞的稳态和缺乏GADD45A会引起狼疮。其他两个的角色 家庭成员GADD45B和GADD45G在自身免疫性疾病中尚不清楚。在Th1细胞中，GADD45B和 TCP信号传导或IL-12和IL-18诱导GADD45G而不是GADD45A。我们发现缺乏 GADD45B和GADD45G导致针对单核细胞增生李斯特菌的Th1细胞数量大大减少。 预期TH1细胞数量很少，我们惊讶地看到GADD45B缺失导致 恶化的实验性过敏性脑脊髓炎（EAE）具有更严重的临床体征，延长了 疾病病程并增加发炎的中枢神经系统中的自动反应性Th1细胞。 GADD45B删除也导致 老鼠的脾脏增大。 GADD45B/GADD45G双重缺陷进一步加剧了这种表​​型和 与GADD45B单缺失相比，老鼠老鼠的脾脏大大增加。扩大 脾脏是由于CD4+ T细胞与活化表型和B细胞的积累。我们的数据 建议GADD45B和GADD45G在调节活化的CD4+ T细胞中起着协同的作用。此外， 我们发现GADD45B和GADD45G抑制了增殖，并且是激活的凋亡所必需的 CD4+ T细胞。在此提案中，我们正在检验以下假设：GADD45蛋白质家族成员GADD45B GADD45G是自身免疫的重要负调节剂。具体我们计划：1。提供确定的 证明GADD45B和GADD45G协调调节自身免疫性疾病，2。 GADD45G对于控制T细胞增殖和EAE中的凋亡至关重要，3。研究分子 通过GADD45B和GADD45G调节Th1细胞增殖和凋亡的机制。规定 GADD45分子家族的外周效应子CD4+ T细胞中的增殖和凋亡提供了一种 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。