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: 10320439
• 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/10320439
• 关键词: 3-Dimensional; Antiparasitic Agents; Apical; Cell Maturation; Cell Nucleus; Cell membrane; Cells; Centrosome; Complex; Cullin Proteins; Cytokinesis; Data; Daughter; Defect; Development; Disease; F Box Domain; F-Box Proteins; Fetal Development; Future; Growth; Guanosine Triphosphate Phosphohydrolases; Immunocompromised Host; Interphase; Life; Membrane; Microscopy; Modeling; Mothers; Names; Organelles; Parasites; Plasmodium; Process; Proteins; Proteomics; Publishing; Research; Resolution; Role; Skeleton; Structure; Testing; Toxoplasma; Trimethoprim-Sulfamethoxazole; Work; base; cell motility; daughter cell; new therapeutic target; novel; oligomycin sensitivity-conferring protein; pathogen; protein complex; receptor; recruit; scaffold; screening; 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的主要机制 严重且危及生命的疾病。寄生虫通过称为内生作用的过程进行复制， 一个母亲体内会形成两个女儿寄生虫。内生作用的关键步骤是形成 子细胞内膜复合体，它是直接位于子细胞内膜复合体的独特细胞器 位于质膜下方，是寄生虫运动和复制所必需的。期间 子细胞发育过程中，新生的 IMC 从称为子细胞的复合物中出现 脚手架（DCS）。尽管 DCS 很重要，但它的特性却很差，而且其组成部分也很少 蛋白质是已知的。在这里，我们假设弓形虫 F-box 蛋白 TgFBXO1 是一种 DCS 的关键组成部分。为了检验我们的假设，我们将确定： i) TgFBXO1 是如何的 针对 DCS，ii) TgFBXO1 如何调节内膜复合物的发育和 组织，以及 iii) 哪些 TgFBXO1 相互作用蛋白对于内膜很重要 复杂的发展。这些研究将共同​​提供深入的机制细节 对重要原生动物病原体的生长至关重要的蛋白质复合物。此外，他们 作为未来研究的跳板，旨在开发新型抗寄生虫药物 通过靶向该复合物发挥作用。