Defining and Exploiting the Circadian Clocks in Malaria Parasites

定义和利用疟疾寄生虫的昼夜节律时钟

• 批准号: 10687634
• 负责人: Filipa Rijo-Ferreira
• 金额: $ 139.91万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687634
• 关键词: Arrhythmia; Behavioral; Bioinformatics; Biological Rhythm; Biology; Cessation of life; Characteristics; Circadian Rhythms; Communicable Diseases; Disease; Erythrocytes; Fever; Foundations; Genetic Screening; Human; Immune; Infection; Knowledge; Leishmaniasis; Malaria; Metabolic; Metabolism; Methods; Molecular; Organism; Parasites; Parasitic Diseases; Parasitic infection; Parasitology; Pathogenesis; Periodicals; Periodicity; Persons; Pharmaceutical Preparations; Physiological; Planet Earth; Process; Public Health; Regulation; Research; Role; Rotation; Sleep Wake Cycle; Symptoms; Toxoplasmosis; Work; circadian biology; circadian pacemaker; driving force; experience; fitness; improved; innovation; insight; mutant; novel strategies; pathogen; success; transmission process; vector; wasting

Project Summary | Abstract Malaria’s immense public health burden is undisputable with numbers of deaths increasing since 2020, however the mechanism for its characteristic rhythmic fevers remains poorly understood. Earth rotation has been a driving force for organisms to evolve circadian clocks to anticipate daily rhythms. In humans, circadian clocks regulate multiple physiological aspects of biology, including sleep-wake cycles, metabolism, and immune defense. Human’s circadian biology leads to body rhythms experienced by the pathogens that infect us. Malaria, a parasitic disease that kills over half a million people each year, is famous for its periodic fevers. Malarial periodic fevers are a consequence of the synchronous bursting of the host’s red blood cells, containing parasites and metabolic waste. It has long been assumed that malarial periodic fevers and the parasite replication rhythms that cause them were driven by the host’s own circadian rhythms. The existence and role of the malarial parasites’ intrinsic clocks has been unknown. Recent discoveries showed that malaria parasite rhythms are intrinsic. Parasite’s synchronous bursting persists even when infecting a circadian clock mutant arrhythmic host. However, the molecular regulation and functions of malaria clock remains elusive. This led to the hypothesis that the parasite clock is an essential component of parasite biology and a contributor to pathogenesis of parasitic diseases. The overall aim of this proposal is to decode the molecular processes that regulate circadian rhythms in parasites and discover how disrupting their regulatory networks impacts the pathogenesis of malaria and transmission. By using forward-genetics screens, behavioral, molecular and bioinformatic approaches, the molecular machinery of malaria parasites will be identified. This is an emerging new field of research of circadian rhythms in infectious diseases. The fact that multiple parasitic infections show daily rhythms further supports the hypothesis that circadian rhythm in parasites is essential for their biology, fitness and potentially transmission - and that deregulation of this biological rhythm may disrupt their well-orchestrated success in causing infections. This proposal will provide a foundation for discovering parasite clocks in other parasitic diseases such as toxoplasmosis and leishmaniasis. Beyond the significance of this work to basic parasitology discovery, it could also unravel insights on the disease pathogenesis by uncovering the mechanism for malaria’s main fever symptom. Parasitic diseases pose increasing threats to global public health and this innovative research will provide new targets to directly disrupt the rhythms that contribute to the disease.

项目概要 | 摘要 然而，自 2020 年以来，疟疾造成的巨大公共卫生负担无可争议，死亡人数不断增加 其特征性的节律性发热的机制仍然知之甚少。 生物体进化生物钟以预测人类的日常节律的驱动力。 调节生物学的多个生理方面，包括睡眠-觉醒周期、新陈代谢和免疫 人类的昼夜节律会导致感染疟疾的病原体产生身体节律。 疟疾是一种寄生虫病，每年导致超过 50 万人死亡，以周期性发烧而闻名。 周期性发烧是宿主红细胞同步爆发的结果，其中含有寄生虫 长期以来，人们一直认为疟疾的周期性发烧和寄生虫的复制节律有关。 导致它们受到宿主自身昼夜节律驱动的疟疾的存在和作用。 最近的发现表明疟原虫的节律是未知的。 即使在感染生物钟突变型心律失常宿主时，寄生虫的同步爆发仍然存在。 然而，疟疾生物钟的分子调控和功能仍然难以捉摸，这导致了这一假设。 寄生虫时钟是寄生虫生物学的重要组成部分，也是寄生虫发病机制的贡献者 该提案的总体目标是解码调节昼夜节律的分子过程。 寄生虫的节律，并发现破坏其调节网络如何影响疟疾的发病机制 通过使用正向遗传学筛选、行为、分子和生物信息学方法， 疟疾寄生虫的分子机制将被确定，这是一个新兴的研究领域。 传染病的昼夜节律事实上，多种寄生虫感染进一步显示出昼夜节律。 支持这样的假设：寄生虫的昼夜节律对其生物学、健康和潜在的潜力至关重要 传播——这种生物节律的放松管制可能会破坏它们精心策划的成功 该提案将为发现其他寄生虫中的寄生虫时钟提供基础。 弓形体病和利什曼病等疾病超出了这项工作对基础寄生虫学的意义。 发现，它还可以通过揭示疟疾的机制来阐明疾病发病机制 主要发烧症状。寄生虫病对全球公共卫生构成越来越大的威胁，而这种创新。 研究将提供新的目标来直接破坏导致疾病的节律。