Understanding inter-organellar communication in apicomplexan parasites

了解顶复门寄生虫的细胞器间通讯

• 批准号: 10714402
• 负责人: Diego Huet
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714402
• 关键词: Antiparasitic Agents; Biology; Biotinylation; Cell physiology; Cells; Communication; Complement; Complex; Development; Environment; Eukaryota; Event; Evolution; Homeostasis; Knowledge; Laboratories; Life Cycle Stages; Malaria; Mammals; Mediating; Membrane; Metabolic; Modeling; Molecular; Nutrient; Organelles; Organism; Parasites; Pathogenicity; Plastids; Play; Proteins; Research; Role; Site; Structure; Toxoplasma gondii; Toxoplasmosis; Work; Yeasts; cell type; design; human disease; insight; pathogen; protein structure

PROJECT SUMMARY/ABSTRACT Inter-organellar communication is an essential process for cellular function. Inside the cell, organelles can interact through specialized microdomains called membrane contact sites (MCSs). These structures mediate the close apposition of two organellar membranes, allowing the exchange of metabolites. In doing so, MCSs are crucial for cellular homeostasis and metabolic plasticity. However, most of what is known about MCSs comes only from a handful of well-studied metazoans, particularly yeast and mammals. Studying the function and composition of MCSs in other eukaryotes—particularly in divergent lineages possessing phylum-specific organelles—is therefore crucial to gain insights into the mechanisms requiring an independent solution to inter- organellar communication. My group seeks to understand inter-organellar communication in apicomplexans, are a group of parasitic protists that include the causative agents of malaria and toxoplasmosis. In their complex life cycles, many of these organisms transition through a variety of environments as they enter and exit cells in different host species. The ability to propagate within a wide range of cell types relies on the capacity to access nutrients from diverse and changing environments, which underscores the metabolic plasticity of apicomplexans. Most apicomplexans possess a single mitochondrion and an apicoplast, a non-photosynthetic plastid that arose from a secondary endosymbiotic event at least 600 million years ago. Both organelles have been coevolving ever since, and now play crucial roles in the metabolic plasticity and survival of these parasites. Although a close physical interaction between the mitochondrion and the apicoplast has been observed, the molecular identity of this interaction remains elusive. Using the model apicomplexan Toxoplasma gondii, my laboratory aims to identify the molecular effectors mediating the mitochondrion-apicoplast interaction using two different, yet complementary approaches: proximity biotinylation and bimolecular complementation. As the apicoplast is an apicomplexan-specific organelle, the identification of proteins involved in mitochondrion-apicoplast MCSs could provide opportunities for the design of anti-parasitic therapies against these pathogens. Our work will open new scientific venues of apicomplexan biology, and yield insight into the evolution and organellar crosstalk in these organisms.

项目摘要/摘要 掌管间通信是细胞功能的重要过程。在细胞内，细胞器可以 通过称为膜接触位点（MCS）的专用微区域相互作用。这些结构介导 密切占有两个有机膜，允许交换代谢物。这样，MCS是 对于细胞稳态和代谢可塑性至关重要。但是，关于MCS的大多数已知 仅来自少数经过良好的后生动物，尤其是酵母和哺乳动物。研究功能和 MCS在其他真核生物中的组成 - 特别是在具有门特异性的不同谱系中 细胞器 - 因此，至关重要的是了解需要独立解决方案的机制 细胞器通讯。 我的小组试图了解apicomplexans中的欧类间交流，是一群寄生虫 其中包括疟疾和弓形虫病的病因。在他们复杂的生活周期中，其中许多 当生物体进入并退出不同宿主物种的细胞时，它们通过各种环境过渡。这 在广泛的细胞类型中传播的能力取决于从不同的能力获得营养的能力 不断变化的环境，强调了Apicomplexans的代谢可塑性。大多数apicomplexans 具有单一线粒体和一个apicoplast，一种非斑点质体，它来自次级 内共生事件至少在6亿年前。从那以后，两个细胞器就一直在共同发展，现在 在这些寄生虫的代谢可塑性和存活中起关键作用。虽然是紧密的身体互动 已经观察到线粒体和凋亡的apicoplast之间，这种相互作用的分子身份 仍然难以捉摸。 我的实验室使用模型apicomplexan弓形虫Gondii，旨在鉴定分子效应 使用两种不同但互补的方法介导线粒体 - 圆锥体相互作用： 接近生物素化和生物分子完成。由于apicoplast是一种特定于Apicomplexan Organelle，鉴定线粒体 - 圆锥体MCSS的蛋白质可以提供机会 用于针对这些病原体的抗寄生虫疗法的设计。我们的工作将开设新的科学场所 Apicomplexan生物学，并深入了解这些生物体中的进化和细胞器串扰。