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.

弓形虫的不受控制的生长是寄生虫引起 严重且危及生命的疾病。这种寄生虫通过一种称为内生作用的过程进行复制， 其中两个女儿寄生虫在一个单亲母亲体内形成。内生的关键一步是形成 子细胞内膜复合体，这是一种独特的细胞器，直接位于 在质膜下面，是寄生虫运动和复制所必需的。在.期间 子细胞发育，新生的IMC出现在一个名为子细胞的复合体中 脚手架(DCS)。尽管它很重要，但分布式控制系统的特点很差，其成员很少 蛋白质是已知的。这里，我们假设弓形虫F-box蛋白TgFBXO1是一种 集散控制系统的关键组件。为了检验我们的假设，我们将确定：i)TgFBXO1如何 针对DCs，II)TgFBXO1如何调节内膜复合体的发育和 组织，以及III)哪些与TgFBXO1相互作用的蛋白质对内膜起重要作用 复杂的开发。总之，这些研究将为 对重要原生动物病原体的生长至关重要的蛋白质复合体。此外，他们还 为未来旨在开发新型抗寄生虫药物的研究提供了跳板 通过瞄准这个建筑群来发挥作用。