The role of FENDRR in host defense against Mycobacterium tuberculosis infection

FENDRR 在宿主防御结核分枝杆菌感染中的作用

基本信息

批准号：
10559243
负责人：
Yong Cheng
金额：
$ 57.9万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559243
关键词：
Bacterial Infections Binding Biology CCAAT-Enhancer-Binding Protein-beta Cell Culture Techniques Cells Cessation of life Communicable Diseases Data Development Enhancers Gene Transfer Genetic Transcription Goals Growth Homeostasis Homologous Gene Host Defense Human IRE-Binding Protein In Vitro Infection Iron Iron Regulatory Protein 1 Knockout Mice Lung Mammalian Cell Mediating MicroRNAs Modeling Mus Mycobacterium tuberculosis Nucleotides Pathway interactions Proteins Public Health RNA Regulation Reporting Role TLR2 gene Testing Transcript Tuberculosis Untranslated RNA Up-Regulation activating transcription factor adenoviral-mediated fetal in vivo knock-down macrophage microbial mouse model novel overexpression p38 Mitogen Activated Protein Kinase pathogen pathogenic bacteria promoter response transcription factor tuberculosis treatment

项目摘要

PROJECT SUMMARY Mycobacterium tuberculosis (M.tb) is an intracellular bacterial pathogen that causes tuberculosis in humans. Tuberculosis remains a major global public health threat. Annually, there are approximately 10 million active tuberculosis cases and 1.4 million deaths worldwide. The mechanism of host-M.tb interactions remains to be defined. Long noncoding RNAs (lncRNAs) are noncoding transcripts longer than 200 nucleotides. In response to bacterial infections, mammalian cells produce abundant lncRNAs to mediate host-pathogen interactions, which are beneficial or detrimental to host defense. A very limited number of studies have been reported on the role of host lncRNAs in the response to M.tb infection. However, increasing evidence indicates that host lncRNAs are engaged in the host defense against microbial infection in host cells. Our long-term goals are to elucidate the fundamental mechanisms of the host lncRNA-regulated anti-M.tb response in macrophages and investigate the potential application of host lncRNAs as novel host-directed therapies for tuberculosis. Our preliminary data indicate that M.tb infection induces the expression of host lncRNA, fetal-lethal noncoding development regulatory RNA (FENDRR), in mouse and human macrophages in vitro and in vivo. Additionally, FENDRR-knockdown facilitates M.tb growth in mouse and human macrophages in cell culture. Furthermore, FENDRR interacts with host iron-responsive element-binding protein 1(Irp1) and down-regulates host microRNA miR-214 in mouse macrophages post M.tb infection. We hypothesize that FENDRR mediates the anti-M.tb response by controlling intracellular iron availability via interfering with iron-responsive protein IRP1 and by upregulating the anti-M.tb protein enhancer of Zeste homolog 1 (EZH1) through competing with the host microRNA miR-214. We will test our hypothesis using mouse and human macrophage cell culture, and mouse models of tuberculosis. Aim I will investigate the mechanism by which M.tb induces FENDRR expression via the TLR2-Myd88-p38-C/EBPβ axis. Aim II will define the mechanisms by which FENDRR exerts anti-M.tb response. Aim III will evaluate the functional roles and mechanisms of action of FENDRR in mouse models of tuberculosis. The proposed studies will reveal a novel anti-M.tb pathway mediated by host lncRNA FENDRR.

项目概要结核分枝杆菌 (M.tb) 是一种导致人类结核病的细胞内细菌病原体。结核病仍然是全球主要的公共卫生威胁，每年约有 1000 万人患有结核病。全球结核病病例和 140 万人死亡宿主与结核分枝杆菌相互作用的机制仍有待研究。长非编码 RNA (lncRNA) 是长度超过 200 个核苷酸的非编码转录本。对于细菌感染，哺乳动物细胞产生丰富的lncRNA来介导宿主与病原体的相互作用，对宿主防御有益或有害的研究报道数量非常有限。宿主lncRNAs在M.tb感染反应中的作用然而，越来越多的证据表明宿主lncRNAs。参与宿主防御宿主细胞中微生物感染的过程。我们的长期目标是阐明。巨噬细胞中宿主lncRNA调节的抗M.tb反应的基本机制并进行研究我们的初步数据表明宿主lncRNA作为新型宿主导向疗法的潜在应用。表明 M.tb 感染诱导宿主 lncRNA 的表达，这是胎儿致死性非编码发育调节 RNA (FENDRR)，在体外和体内的小鼠和人类巨噬细胞中，FENDRR 敲低。促进 M.tb 在细胞培养物中的小鼠和人类巨噬细胞中生长。此外，FENDRR 还与 M.tb 相互作用。小鼠体内宿主铁反应元件结合蛋白 1 (Irp1) 并下调宿主 microRNA miR-214 M.tb 感染后的巨噬细胞认为 FENDRR 通过控制来介导抗 M.tb 反应。通过干扰铁反应蛋白 IRP1 和上调抗 M.tb 细胞内铁的可用性我们将通过与宿主 microRNA miR-214 竞争来测试 Zeste 同源物 1 (EZH1) 的蛋白质增强子。我们的假设使用小鼠和人类巨噬细胞培养物以及小鼠结核病模型。研究 M.tb 通过 TLR2-Myd88-p38-C/EBPβ 轴诱导 FENDRR 表达的机制。目标 II 将定义 FENDRR 发挥抗 M.tb 反应的机制，目标 III 将评估 FENDRR 的机制。 FENDRR 在小鼠结核病模型中的功能作用和作用机制。将揭示一种由宿主 lncRNA FENDRR 介导的新型抗 M.tb 途径。