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: 10083185
• 负责人: Ira J Blader
• 金额: $ 66.08万
• 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/10083185
• 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.

不受控制的毒质量生长是寄生虫引起的主要机制 严重和威胁生命的疾病。寄生虫通过称为内部发育的过程复制， 在一个单亲母亲中形成两个女儿寄生虫。内部发育的关键步骤是形成 女儿细胞内膜复合物的独特细胞器，直接位于 在质膜下方，是寄生虫运动和复制所必需的。期间 女儿细胞开发，新生的IMC来自一个名为女儿细胞的建筑群 脚手架（DCS）。尽管其重要性，但DC的特征很差，其组成部分很少 蛋白质是已知的。在这里，我们假设弓形虫F-box蛋白TGFBXO1是一个 DC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 针对DCS，ii）TGFBXO1如何调节内膜复合物的发展和 组织，以及iii）哪种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​​提供深入的机理细节 蛋白质复合物对于重要的原生动物病原体的生长至关重要。此外，他们 被用作未来研究的跳板，旨在开发新型的抗寄生虫药物 通过瞄准该复合物来功能。