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Immune Regulation by Gadd45b and Gadd45g

Gadd45b 和 Gadd45g 的免疫调节

基本信息

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
项目类别：
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

项目摘要

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