The Organization and Function of the Toxoplasma Daughter Cell Scaffold

弓形虫子细胞支架的组织和功能

• 批准号: 10533770
• 负责人: Ira J Blader
• 金额: $ 64.6万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-08 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533770
• 关键词: 3-Dimensional; Antiparasitic Agents; Apical; Cell Maturation; Cell Nucleus; Cell membrane; Cells; Centrosome; Complex; Cullin Proteins; Cytokinesis; Cytoplasm; Data; Daughter; Defect; Development; Disease; F Box Domain; F-Box Proteins; Fetal Development; Future; Growth; Guanosine Triphosphate Phosphohydrolases; Immunocompromised Host; Interphase; Life; Membrane; Modeling; Mothers; Names; Organelles; Parasites; Plasmodium; Process; Proteins; Proteomics; Publishing; Research; Role; Skeleton; Structure; Testing; Toxoplasma; Trimethoprim-Sulfamethoxazole; Work; cell motility; daughter cell; new therapeutic target; novel; oligomycin sensitivity-conferring protein; pathogen; protein complex; receptor; recruit; scaffold; screening; superresolution microscopy; ubiquitin-protein ligase

Uncontrolled Toxoplasma growth is the primary mechanism by which the parasite causes severe and life-threatening disease. The parasite replicates by a process termed endodyogeny, where two daughter parasites form within a single mother. A key step in endodyogeny is formation of the daughter cell inner membrane complex, which is an unique organelle that lies directly underneath the plasma membrane and is required for parasite motility and replication. During daughter cell development, the nascent IMC emerges from a complex named the daughter cell scaffold (DCS). Despite its importance, the DCS is poorly characterized and few of its constituent proteins are known. Here, we hypothesize that the Toxoplasma F-box protein, TgFBXO1, is a critical component of the DCS. To test our hypothesis, we will determine: i) how TgFBXO1 is targeted to the DCS, ii) how TgFBXO1 regulates inner membrane complex development and organization, and iii) which TgFBXO1-interacting proteins are important for inner membrane complex development. Together, these studies will provide in depth mechanistic detail for a protein complex that is critical for growth of an important protozoan pathogen. Furthermore, they were serve as a springboard for future studies aimed at developing novel anti-parasitic drugs that function by targeting this complex.

不受控制的弓形虫生长是寄生虫引起 严重和危及生命的疾病。寄生虫通过一种称为内分泌的过程进行复制， 一个母亲体内会产生两个寄生虫女儿内膜异位症的关键步骤是形成 子细胞内膜复合体，这是一种独特的细胞器， 在质膜下，并且是寄生虫运动和复制所需的。期间 在子细胞发育过程中，新生的IMC从一个名为子细胞的复合体中出现 支架（DCS）。尽管它的重要性，DCS是穷人的特点，很少有其组成部分， 蛋白质已知。在这里，我们假设弓形虫F-box蛋白TgFBXO 1是一种 DCS的重要组成部分。为了检验我们的假设，我们将确定：i）TgFBXO 1是如何被 靶向DCS，ii）TgFBXO 1如何调节内膜复合物的发育， 组织，和iii）哪些TgFBXO 1相互作用蛋白对于内膜是重要的 复杂的发展。总之，这些研究将提供深入的机制细节， 一种对重要的原生动物病原体的生长至关重要的蛋白质复合物。而且他们 作为未来研究的跳板，旨在开发新的抗寄生虫药物， 以这个复杂的系统为目标。