Development and maintenance of chronic toxoplasmosis

慢性弓形虫病的发展和维持

• 批准号: 10181740
• 负责人: Sebastian Lourido
• 金额: $ 68.25万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10181740
• 关键词: 5' Untranslated Regions; Address; Binding; Brain; CRISPR screen; Categories; Cell Culture Techniques; Chromatin; Chronic; Complement; Cyst; Data; Development; Disease; Disease Reservoirs; Down-Regulation; Elements; Environmental Risk Factor; Event; Exposure to; Failure; Foundations; Future; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Immunocompetent; Immunocompromised Host; Individual; Infection; Lesion; Licensing; Life; Link; Maintenance; Mediating; Messenger RNA; Molecular; Monitor; Mus; Mutation Analysis; National Institute of Allergy and Infectious Disease; Nucleic Acid Binding; Parasites; Pathway interactions; Population; Prevalence; Process; Proteins; Proteomics; RNA; Recurrence; Regulation; Regulatory Pathway; Reporter; Resistance; Resolution; Ribosomes; Role; Stress; Structure; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Transcript; Transcriptional Regulation; Translational Regulation; Translations; Video Microscopy; Virulence; Work; acute infection; alkalinity; base; biodefense; curative treatments; insight; mouse model; prevent; programs; promoter; response; ribosome profiling; screening; transcription factor; transcriptome sequencing

7. PROJECT SUMMARY/ABSTRACT Chronic Toxoplasma gondii infections are widespread and their reactivation can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent. The recently identified master regulator of chronic differentiation, BFD1, provides an unprecedented opportunity to investigate the molecular events that establish and maintain chronic T. gondii infections. BFD1 is necessary for chronic differentiation in cell culture and in mouse models of infection, and its expression is sufficient to induce chronic differentiation. Consistent with a sustained requirement for BFD1 during chronic stage maintenance, the differentiation program is reversed upon conditional down-regulation of BFD1. Preliminary results indicate that BFD1 is post-transcriptionally controlled through its 5′ UTR, leading to the hypothesis that translational regulation of BFD1 is fundamental to the development and maintenance of chronic T. gondii stages. This proposal seeks to integrate BFD1 into a broader regulatory network through three complementary aims. Aim 1 will examine the sequence elements, secondary RNA structures, and ribosomal occupancy dynamics that mediate BFD1 translational regulation. Aim 2 will use conditional depletion of BFD1 to characterize transcriptional and proteomic changes that mediate reactivation, and the molecular circuits that maintain the differentiated state. Finally, Aim 3 will extend the regulatory pathways that control differentiation by screening for genes involved in the translational regulation of BFD1 and further examining the function of transcription factors directly regulated by BFD1. The overarching goal of this comprehensive analysis is to understand the conditions that promote chronic differentiation and license the development of curative therapies against toxoplasmosis.

7.项目摘要/摘要 慢性弓形虫感染广泛存在，它们的重新激活可导致危及生命的疾病 免疫功能低下的个体和复发性眼部病变中的免疫活性。最近确认的 慢性分化的主要调节因子BFD1提供了前所未有的机会来研究 建立和维持慢性弓形虫感染的分子事件。BFD1对于慢性疾病是必要的 在细胞培养和小鼠感染模型中的分化，其表达足以诱导慢性 差异化。与慢性阶段维护期间对BFD1的持续需求一致， 在有条件下调BFD1的情况下，分化程序被逆转。初步结果表明，BFD1 是通过其5‘UTR转录后控制的，导致假设BFD1的翻译调控 是弓形虫慢性阶段发育和维持的基础。这项提议寻求将 通过三个相辅相成的目标将BFD1纳入更广泛的监管网络。目标1将检查序列 介导BFD1翻译的元件、二级RNA结构和核糖体占据动力学 监管。目标2将使用BFD1的条件性缺失来表征转录和蛋白质组的变化 调节再激活，以及维持分化状态的分子回路。最后，目标3将延长 通过筛选参与BFD1翻译调控的基因来控制分化的调控途径 进一步检测BFD1直接调控的转录因子的功能。这件事的首要目标是 综合分析是了解促进慢性分化的条件，并许可 弓形虫病治疗方法的发展。