Development and maintenance of chronic toxoplasmosis

慢性弓形虫病的发展和维持

• 批准号: 10374148
• 负责人: Sebastian Lourido
• 金额: $ 67.13万
• 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/10374148
• 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 慢性弓形虫感染是广泛的，它们的重新激活会导致威胁生命的疾病 免疫功能低下的个体和免疫能力的复发性眼病变。最近确定的 长期差异化的主要监管者BFD1为调查调查提供了前所未有的机会 建立和维持慢性T. gondii感染的分子事件。 BFD1对于慢性是必需的 细胞培养和小鼠感染模型的分化，其表达足以诱导慢性 分化。与在慢性阶段维护期间对BFD1的持续要求一致 在BFD1的有条件下调时，差异化程序会逆转。初步结果表明BFD1 在转录后通过其5'UTR进行控制，导致假设翻译了BFD1的调节 对于慢性T. gondii阶段的发展和维护至关重要。该建议旨在整合 BFD1通过三个完整目标进入更广泛的监管网络。 AIM 1将检查序列 元素，次级RNA结构和核糖体占用动力学，介导BFD1翻译 规定。 AIM 2将使用BFD1的条件部署来表征转录和蛋白质组学变化 培养基重新激活，以及维持分化状态的分子电路。最后，AIM 3将扩展 通过筛选涉及BFD1翻译调节的基因来控制分化的调节途径 并进一步研究了直接由BFD1调节的转录因子的功能。总体目标 全面的分析是了解促进长期差异和许可的条件 针对弓形虫病的治疗疗法的开发。