Diversity Supplement R00 - Brianna Parrington

多样性补充 R00 - Brianna Parrington

• 批准号: 10755066
• 负责人: Filipa Rijo-Ferreira
• 金额: $ 6.7万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755066
• 关键词: Arrhythmia; Bacteria; Behavior; Cell Cycle; Chronic; Circadian Rhythms; Compensation; Culicidae; Data; Development; Disease; Environment; Erythrocytes; Fever; Gene Expression; Gene Mutation; Genes; Human; In Vitro; Infection; Jet Lag Syndrome; Longevity; Malaria; Metabolic; Mutation; Organism; Parasites; Parasitic Diseases; Parasitic infection; Periodicity; Physiological; Plasmodium; Population; Process; Recurrence; Research; Rodent; Rupture; Signal Transduction; Temperature; Testing; asexual; circadian pacemaker; experimental study; fitness; in vivo; mutant; parasite invasion; success

Contact PD/PI: Rijo-Ferreira, Filipa Project Summary Malaria is a deadly parasitic disease. The parasite population coordinately ruptures the red blood cells (RBCs), reinvades new ones and replicates until their cycle is completed, and then a new burst of RBCs occurs. The result is a paroxysmal fever that recurs with the same periodicity as the parasite asexual cell cycle: 48h or 72h for human-specific Plasmodium species and 24h for rodent-specific Plasmodium species. The mechanism for parasite synchronicity, which is central to this phenomenon, remains unknown. Because the asexual cell cycle across Plasmodium species has a duration that is multiple of 24h, this led me to hypothesize that the mechanism for fever periodicity is an endogenous circadian clock of the parasite. Circadian clocks regulate multiple physiological functions, from gene expression to behavior. Having circadian clocks that anticipate rhythmic changes in the environment is an evolutionary advantage for organisms. From bacteria to humans, mutations in clock components or desynchrony between the clock and the environment (e.g. chronic jet-lag) leads to reduced fitness, metabolic disruption, and shorter lifespan. Similarly, it has also been shown that a mismatch between host and parasite rhythms is detrimental for malaria parasite infection success. We demonstrated the existence of an intrinsic circadian clock in malaria parasites. Even in hosts whose circadian rhythms are disrupted through clock gene mutations, the parasite gene expression rhythms persist. In a wildtype infections the parasite expresses rhythmically 80% of its genes, whereas in an arrhythmic mutant host infection the parasite maintains rhythmic the expression of 60% of its genes, strongly supporting the existence of an intrinsic mechanism in the parasites regulating this phenomena. My findings have also highlighted that parasites sense and adjust their intrinsic clock to the host rhythms, if those rhythms exist. In addition, my preliminary data shows that these gene expression rhythms are not only due to the cell cycle of the parasite as previously assumed, but the rhythms also persist when parasites are in a quiescent state. In this proposal, I will test a central hypothesis that malaria synchronicity is the result of both the integration of host signals and an intrinsic circadian clock. Through in vivo and in vitro experiments, I will determine whether malaria parasites have an intrinsic clock independent of cell cycle by testing if parasite rhythms persist in the mosquito stage of the infection, and whether such rhythms are indeed circadian rhythms by testing for temperature compensation. These studies will generate a comprehensive framework to resolve a long-standing question in the malaria field. More broadly, by dissecting whether the periodicity of fevers is driven by host signals alone or by both host signals and an internal parasite clock, these studies will guide strategies to disrupt the synchronicity of the parasite. This will not only provide lessons of host-parasite interactions as it will potentially provide complementary approaches to tackle this deadly disease. Project Summary

联系PD/PI：Rijo-Ferreira，Filipa 项目摘要 疟疾是一种致命的寄生疾病。寄生虫种群协同破裂红细胞（RBC）， 重新启动新的并复制直到其周期完成，然后发生新的RBC。这 结果是阵发性发烧，其周期性与寄生虫无性细胞周期相同：48h或72h 用于人类特异性疟原虫，24小时用于啮齿动物特异性疟原虫物种。机制 寄生虫同步性是这种现象的核心，仍然未知。因为无性细胞周期 整个疟原虫的持续时间为24小时，这导致我假设该机制 为了发烧，周期性是寄生虫的内源性昼夜节律。 昼夜节律时钟调节从基因表达到行为的多种生理功能。有昼夜节律 预期环境有节奏变化的时钟是生物体的进化优势。从 对人类的细菌，时钟组分的突变或时钟与环境之间的不融合（例如 慢性喷射滞后）导致健身，代谢破坏和寿命较短​​。同样，也已经 表明宿主和寄生虫节奏之间的不匹配对疟疾寄生虫感染的成功有害。 我们证明了在疟疾寄生虫中存在固有的昼夜节律。即使在主持人 昼夜节律通过时钟基因突变破坏了，寄生基因表达节奏持续存在。在 野生型感染寄生虫以节奏的80％的基因表示，而在心律失常突变宿主中 感染寄生虫保持节奏60％的基因的表达，强烈支持存在 调节这种现象的寄生虫的内在机制。我的发现也强调了 如果存在这些节奏，寄生虫将其内在时钟感知到宿主节奏。另外，我的 初步数据表明，这些基因表达节奏不仅是由于寄生虫的细胞周期造成的 以前假定，但是当寄生虫处于静止状态时，节奏也持续存在。在这个建议中，我将 测试疟疾同步性的中心假设是宿主信号和一个整合的结果 固有的昼夜节律。通过体内和体外实验，我将确定是否疟原虫 通过测试寄生虫节奏在蚊子阶段是否持续存在，具有独立于细胞周期的固有时钟 感染以及这种节奏是否确实是通过测试温度补偿的昼夜节律。 这些研究将产生一个全面的框架，以解决疟疾领域的长期问题。 更广泛地，通过剖析发烧的周期性是单独由主机信号驱动还是由两个主机驱动 信号和内部寄生虫时钟，这些研究将指导策略破坏同步性 寄生虫。这不仅将提供宿主 - 寄生虫互动的课程，因为它可能会提供 解决这种致命疾病的互补方法。 项目摘要