Development and maintenance of chronic toxoplasmosis

慢性弓形虫病的发展和维持

• 批准号: 10579245
• 负责人: Sebastian Lourido
• 金额: $ 65.98万
• 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/10579245
• 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; biodefense; curative treatments; insight; mouse model; posttranscriptional; 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.项目总结/摘要 慢性弓形虫感染是广泛的，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免疫活性的复发性眼部病变。最近发现的 慢性分化的主要调节因子BFD 1提供了一个前所未有的机会， 分子事件，建立和维持慢性T。弓形虫感染BFD 1是慢性 在细胞培养物和小鼠感染模型中，其表达足以诱导慢性分化， 分化与慢性期维持期间对BFD 1的持续需求一致， 分化程序在BFD 1的条件性下调后逆转。初步结果表明，BFD 1 通过其5′ UTR进行转录后调控，导致BFD 1的翻译调控 对慢性T细胞的发展和维持至关重要。弓形虫分期该提案旨在整合 BFD 1通过三个互补的目标纳入更广泛的监管网络。目标1将检查序列 介导BFD 1翻译的元件、二级RNA结构和核糖体占据动力学 调控目标2将使用BFD 1的条件性缺失来表征转录和蛋白质组学变化， 介导再激活，以及维持分化状态的分子回路。最后，目标3将扩展 通过筛选参与BFD 1翻译调控的基因来控制分化的调控途径 并进一步研究由BFD 1直接调节的转录因子的功能。这个项目的首要目标是 综合分析是为了了解促进慢性分化和许可证的条件， 发展抗弓形虫病的治疗方法。