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虫病。寄生虫群体协调地破坏红细胞（RBC）， 重新侵入新的红细胞并复制，直到它们的循环完成，然后发生新的红细胞爆发。的 结果是阵发性发热，其复发周期与寄生虫无性细胞周期相同：48小时或72小时 人类特异性疟原虫种属为24 h，啮齿动物特异性疟原虫种属为24 h。机制 寄生虫的同步性是这一现象的核心，它仍然是未知的。因为无性细胞周期 在疟原虫物种之间的持续时间是24小时的倍数，这使我假设该机制 对于发烧周期性是寄生虫的内源性生物钟。 生物钟调节多种生理功能，从基因表达到行为。具有昼夜节律 生物钟能够预测环境的节奏变化，这是生物体在进化上的优势。从 细菌对人类的影响，生物钟组件的突变或生物钟与环境之间的差异（例如， 慢性时差）导致健康下降、代谢紊乱和寿命缩短。同样，它也被 表明宿主和寄生虫节律之间的不匹配对疟原虫感染的成功是有害的。 我们证明了疟疾寄生虫中存在固有的生物钟。即使在那些 当生物钟基因突变破坏昼夜节律时，寄生虫基因表达节律持续存在。中 野生型感染的寄生虫有节律地表达80%的基因，而在寄生虫突变宿主中， 感染寄生虫保持其基因的60%的节奏表达，强烈支持存在 寄生虫调节这种现象的内在机制。我的研究结果还强调， 如果宿主的生物钟存在的话，寄生虫会根据宿主的生物钟感应并调整自己的生物钟。另外我 初步数据显示，这些基因表达节律不仅是由于寄生虫的细胞周期， 以前假设，但节奏也坚持寄生虫处于静止状态。在这份提案中，我将 检验一个中心假设，即疟疾的同步性是宿主信号整合的结果， 内在生物钟通过体内和体外实验，我将确定是否疟疾寄生虫 有一个内在的时钟独立于细胞周期，通过测试如果寄生虫的节奏持续在蚊子阶段， 感染，以及通过测试温度补偿来确定这种节律是否确实是昼夜节律。 这些研究将产生一个综合框架，以解决疟疾领域的一个长期问题。 更广泛地说，通过分析发烧的周期性是由宿主信号单独驱动还是由两个宿主信号驱动， 信号和内部寄生虫时钟，这些研究将指导策略，以破坏同步性， 寄生虫这将不仅提供宿主-寄生虫相互作用的教训，因为它将潜在地提供 采取互补的方法来对付这种致命的疾病。 项目摘要