TET2 in Host Defense Against Infection

TET2 在宿主防御感染中的作用

• 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
• 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

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 了解宿主对病原体防御的分子机制对于研究病原体的生物学特性具有重要意义。 开发新的抗感染疗法。I型干扰素（α/β）和II型干扰素（IFNγ）是 参与多种细胞过程调节的强效细胞因子，包括抗病毒、抗肿瘤和 免疫调节功能。干扰素通过JAK-STAT信号通路调节转录， 超过2000个干扰素刺激基因（ISG）的激活。许多实验室的研究表明， 许多ISG在宿主防御病原体中的重要作用，包括IFNγ诱导的 65 kD鸟苷酸结合蛋白（GBP）家族。然而，选择性调节的分子机制 在宿主防御过程中抗感染ISG的诱导知之甚少。 十十一易位（泰特）蛋白家族是甲基胞嘧啶二氧合酶，其功能是 通过调节胞嘧啶羟甲基化促进DNA去甲基化。先前的研究 证明泰特蛋白在干细胞和肿瘤发生的调节中起重要作用。我 实验室最近发现了TET 2在宿主防御中的意想不到的作用。我们发现Tet 2 TET 2缺乏导致对细菌和病毒病原体的保护增强，并且TET 2特异性地 影响响应IFNγ刺激的Gbp基因的诱导。这个应用程序是为了探索一个 TET 2在IFN信号传导和宿主防御病原性感染中的作用以前未被认识。我们 我建议测试一个新的假设，即TET 2的功能是通过选择性地抑制宿主免疫力。 调节IFN介导的基因转录的子集。具体来说，我们将研究 TET 2介导的Gbp基因在宿主防御中的调节，我们将进一步描述TET 2在宿主防御中的作用。 病原体感染使用动物模型。这些及时的研究，如果成功完成，将揭示一个 新的分子机制在宿主防御，并将提高我们的能力，设计更有效的抗- 感染治疗