TET2 in Host Defense Against Infection

TET2 在宿主防御感染中的作用

• 批准号: 9397516
• 负责人: KE SHUAI
• 金额: $ 18.42万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/9397516
• 关键词: Affect; Animal Model; Anti-Bacterial Agents; Anti-Infective Agents; Antiviral 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

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.

项目摘要 了解针对病原体宿主防御涉及的分子机制对于 新型抗感染疗法的发展。 I型干扰素（α/β）和II型干扰素（IFNγ）为 参与调节多个细胞过程的潜在细胞因子，包括抗病毒，抗肿瘤和 免疫调节功能。 IFNS通过JAK-STAT途径发出信号，以调节转录 超过2000个干扰素刺激的基因（ISGS）的激活。许多实验室的研究已经确定 许多ISG在针对病原体的宿主防御中的重要作用，包括IFNγ诱导 65KD鸟甘酯结合蛋白（GBP）家族。但是，有选择性调节的分子机制 在宿主防御期间，抗感染ISG的诱导知之甚少。 蛋白质的十个易位（TET）家族是甲基环胞嘧啶的二氧化碳，起作用 通过调节性胞嘧啶羟甲基促进DNA脱甲基化。先前的研究已有 证明TET蛋白在调节干细胞和肿瘤发生中起着重要作用。我的 实验室最近发现了TET2在宿主防御中的意外作用。我们证明了TET2 缺乏可增强对细菌和病毒病原体的保护，并特别是TET2 影响IFNγ模拟的诱导GBP基因的诱导。此应用程序是探索 TET2在IFN信号传导和宿主防御致病感染中的先前未识别的作用。我们 提议测试一个新的假设，即TET2功能可以通过选择性抑制宿主免疫 IFN介导的基因转录子集的调节。具体而言，我们将研究 TET2介导的GBP基因在宿主防御中的调节，我们将进一步表征TET2在 使用动物模型的致病感染。这些及时的研究，如果成功完成，将发现 宿主防御中的新分子机制，并将提高我们设计更有效抗的能力 感染疗法。