THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE

ICSBP 在粘膜免疫反应中的作用

基本信息

批准号：
8136665
负责人：
HUABAO XIONG
金额：
$ 21.79万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8136665
关键词：
Agreement Antibodies Automobile Driving Binding Cells Chronic Colitis Controlled Study Crohn&apos s disease Dendritic Cells Development Disease Environment Family Gene Expression Generations Genus Cola Germ-Free Goals Host Defense Human IFN consensus sequence binding protein IL10 gene Immune Immune response Immunologics Individual Inflammation Inflammatory Inflammatory Response Inflammatory disease of the intestine Interferons Interleukin-10 Interleukin-12 Knockout Mice Lamina Propria Ligands Mediating Messenger RNA Modeling Molecular Mononuclear Mucosal Immune Responses Mucositis Mus Pathway interactions Patients Peptides Play Production Proteins Reagent Regulation Regulatory T-Lymphocyte Reporting Role Signal Pathway Signal Transduction Site Structure Sulfonic Acids TLR4 gene TRAF6 gene Therapeutic Effect Toll-like receptors Trinitrobenzenes Ubiquitin Ubiquitination cytokine in vivo macrophage microbial mouse model multicatalytic endopeptidase complex pathogen promoter therapeutic target transcription factor ubiquitin-protein ligase

项目摘要

The IFN consensus sequence binding protein (ICSBP/IRF-8), which belongs to the interferon regulatory factor family of transcription factors, is essential for a Thl immune response. ICSBP plays an important role in the host defense against microbial pathogens, but the exact roles of ICSBP in inflammation and chronic inflammatory diseases are still not clear. IL-10-/- mice, which develop colitis characterized by increased Thl cytokines, mimic many aspects of human Crohn's disease (CD). The importance of ICSBP in the development of colitis is shown by the lack of disease in ICSBP and IL-10 double knockout mice. In addition, ICSBP mRNA and protein are highly expressed in the colons of IL-10-/- mice with colitis, while expression of IL-12 and iNOS is significantly compromised in ICSBP/IL-10 double KO mice. In agreement with these results, patients with CD have significantly higher ICSBP expression than normal individuals. ICSBP is active in several loci. ICSBP interacts with TRAF6 in the TLR4 pathway, and binds to ISRE sites in the iNOS and IL-12 p40 promoters, activating the expression of these genes. In addition, we find that ICSBP is ubiquitinated by the E3 ligase Cbl, resulting in its degradation by the proteasome. To expore ICSBP as a suitable target for therapy in CD, this proposal is structured around three aims: 1) We will analyze the regulation of ICSBP expression in macrophages and dendritic cells activated with various TLR and NOD2 ligands. In addition, we will define the role of ICSBP in the generation of regulatory T cells. 2) We will define the function of Cbl in the control of Thl immune immune response and analyze the role of Cbl in the development of colitis. 3) We will define the therapeutic effects of TLR4 and ICSBP inhibition by cell-permeable peptide reagent in vivo in murine colitis models. These studies will advance our understanding the role of ICSBP in the mucosal immune response, and may identify ICSBP as a new target for therapy in CD.

IFN共有序列结合蛋白（ICSBP/IRF-8），属于干扰素转录因子的调节因子家族对于Thl免疫反应至关重要。 ICSBP 在宿主防御微生物病原体方面发挥着重要作用，但确切的 ICSBP 在炎症和慢性炎症性疾病中的作用尚不清楚。 IL-10-/- 患上以Thl细胞因子增加为特征的结肠炎的小鼠在许多方面都模仿人类克罗恩病（CD）。显示了 ICSBP 在结肠炎发展中的重要性 ICSBP 和 IL-10 双敲除小鼠中缺乏疾病。此外，ICSBP mRNA 和蛋白在患有结肠炎的IL-10-/-小鼠的结肠中高表达，而表达在 ICSBP/IL-10 双 KO 小鼠中，IL-12 和 iNOS 的表达显着受损。同意根据这些结果，CD 患者的 ICSBP 表达显着高于正常人个人。 ICSBP 在多个位点具有活性。 ICSBP 与 TLR4 通路中的 TRAF6 相互作用，并与 iNOS 和 IL-12 p40 启动子中的 ISRE 位点结合，激活这些基因。此外，我们发现 ICSBP 被 E3 连接酶 Cbl 泛素化，从而导致它被蛋白酶体降解。为了揭示 ICSBP 作为 CD 治疗的合适靶点，该提案围绕三个目标构建：1）我们将分析 ICSBP 的监管在用各种 TLR 和 NOD2 配体激活的巨噬细胞和树突状细胞中表达。此外，我们将定义 ICSBP 在调节性 T 细胞生成中的作用。 2）我们会定义Cbl在控制Thl免疫免疫反应中的功能并分析 Cbl 在结肠炎发展中的作用。 3）我们将定义TLR4的治疗效果和在小鼠结肠炎模型中体内细胞渗透性肽试剂对 ICSBP 的抑制作用。这些研究将增进我们对 ICSBP 在粘膜免疫反应中的作用的理解，并可能将 ICSBP 确定为 CD 治疗的新靶点。