TET2 in Host Defense Against Infection

TET2 在宿主防御感染中的作用

基本信息

批准号：
9233717
负责人：
KE SHUAI
金额：
$ 22.27万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-13 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233717
关键词：
Affect Animal Model Anti-Bacterial Agents Anti-Infective Agents Bacterial Infections Binding Proteins Bone Marrow Cell physiology Cytosine DNA Development GBP1 gene Gene Expression Gene Expression Regulation Gene Family Genes Genetic Transcription Host Defense Immune response Immunity Infection Interferon Type I Interferon Type II Interferon-alpha Interferons Knockout Mice Laboratories Link Listeria monocytogenes Listeriosis Mediating Molecular Pathogenicity Pathway interactions Play Protein Family Protein translocation Proteins Public Health Regulation Research Resistance Role STAT1 gene Signal Pathway Signal Transduction Specificity Stem cells Testing Time Transcriptional Activation Viral Viral Physiology Virus Virus Diseases cytokine demethylation design effective therapy guanylate immunoregulation influenzavirus knockout animal macrophage member novel novel strategies novel therapeutics pathogen response tumor tumorigenesis

项目摘要

Project Summary Understanding the molecular mechanisms involved in host defense against pathogens is important for the development of novel anti-infective therapies. Type I interferon (α/β) and type II interferon (IFNγ) are potent cytokines involved in the regulation of multiple cellular processes, including anti-viral, anti-tumor, and immunomodulatory functions. IFNs signal through the JAK-STAT pathways to regulate the transcriptional activation of over 2000 interferon-stimulated genes (ISGs). Studies from many laboratories have identified the important role of a number of ISGs in host defense against pathogens, including the IFNγ-inducible 65kD guanylate-binding protein (GBP) family. However, the molecular mechanism that selectively regulates the induction of anti-infective ISGs during host defense is poorly understood. The Ten-eleven translocation (TET) family of proteins are methylcytosine dioxygneases that function to facilitate DNA demethylation through regulating cytosine hydroxymethylation. Previous studies have demonstrated that TET proteins play important roles in the regulation of stem cells and tumorigenesis. My laboratory has recently discovered an unexpected role of TET2 in host defense. We showed that Tet2 deficiency results in enhanced protection against bacterial and viral pathogens, and that TET2 specifically affects the induction of the Gbp genes in response to IFNγ stimulation. This application is to explore a previously unrecognized role of TET2 in in IFN signaling and host defense against pathogenic infection. We propose to test a novel hypothesis that TET2 functions to suppress host immunity through the selective regulation of a subset of IFN-mediated gene transcription. Specifically, we will study the molecular basis of TET2-mediated regulation of Gbp genes in host defense, and we will further characterize the role of TET2 in pathogenic infections using animal models. These timely studies, if successfully completed, will uncover a novel molecular mechanism in host defense, and will advance our ability to design more effective anti- infective therapies.

项目概要了解宿主防御病原体的分子机制对于新型抗感染疗法的开发正在进行中。有效的细胞因子参与多种细胞过程的调节，包括抗病毒、抗肿瘤和 IFN 通过 JAK-STAT 途径发出信号来调节转录。许多实验室的研究已经确定了 2000 多个干扰素刺激基因 (ISG) 的激活。许多 ISG 在宿主防御病原体（包括 IFNγ 诱导型）中发挥重要作用然而，65kD 鸟苷酸结合蛋白（GBP）家族的分子机制是选择性调节的。人们对宿主防御过程中抗感染 ISG 的诱导知之甚少。十十一易位 (TET) 蛋白家族是甲基胞嘧啶双加氧酶，其功能是先前的研究表明，通过调节胞嘧啶羟甲基化来促进 DNA 去甲基化。 TET蛋白在干细胞和肿瘤发生的调节中发挥重要作用。实验室最近发现 TET2 在宿主防御中发挥着意想不到的作用。缺乏导致增强对细菌和病毒病原体的保护，而 TET2 特别影响 Gbp 基因响应 IFNγ 刺激的诱导。 TET2 在 IFN 信号传导和宿主防御病原体感染中的作用此前未被认识。提出测试一个新的假设，即 TET2 通过选择性抑制宿主免疫的功能具体而言，我们将研究 IFN 介导的基因转录子集的分子基础。 TET2介导的Gbp基因在宿主防御中的调节，我们将进一步描述TET2在宿主防御中的作用这些使用动物模型进行的及时研究如果成功完成，将揭示一个问题。宿主防御的新分子机制，并将提高我们设计更有效的抗宿主病毒的能力感染疗法。