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Exploring the function of a novel tyrosine kinase like (TKL) protein in Toxoplasma endodyogeny

探索新型酪氨酸激酶样 (TKL) 蛋白在弓形虫内生过程中的功能

基本信息

批准号：
10617290
负责人：
Rajshekhar Gaji
金额：
$ 24万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-03 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617290
关键词：
Acute Affect Attenuated Biogenesis Biology Blindness Cell Cycle Cell division Cells Child Complement Complex Cytokinesis Cytoplasm Cytoskeleton Cytosol Data Daughter Defect Development Electron Microscopy Elements Encephalitis Enzymes Eukaryota Event Family Genes Goals Immunofluorescence Immunologic Immunologic Deficiency Syndromes Impaired cognition Impairment In Vitro Individual Infection Inflammation Invaded Life Life Cycle Stages Light Lytic Phase Mammalian Cell Mass Spectrum Analysis Membrane Microscopy Microtubules Mitosis Monitor Morphology Newborn Infant Parasites Parents Pathogenesis Pathology Phase Phosphorylation Phosphotransferases Play Pregnant Women Process Protein Family Protein Tyrosine Kinase Proteins Regulation Research Role Shapes Signal Pathway Signal Transduction Spontaneous abortion Testing Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Vacuole Virulence Virulence Factors Work abortion attenuation daughter cell effective therapy fitness human pathogen in vitro Assay member mouse model mutant novel novel therapeutics pathogen

项目摘要

PROJECT SUMMARY/ABSTRACT Toxoplasma gondii is an important human pathogen that divides by a unique mode of cell division called endodyogeny that is quite distinct from binary fission that occurs in mammalian cells. Since Toxoplasma division is divergent from higher eukaryotes, a better understanding of this complex process and identification of its key components and their mode of regulation would potentially open doors for selective strategies to disrupt infection. TgTKL4 is a member of tyrosine kinase like (TKL) family protein in Toxoplasma that localizes to parasite cytoplasm with its expression mainly confined to synthesis (S), mitosis/cytokinesis (M/C) phases of the cell cycle. Interestingly, loss of this kinase causes defects in cell division that results in misshapen parasites with compromised fitness and attenuated virulence. Specifically, TgTKL4 null mutants with abnormal morphology display significant defects in in vitro propagation suggesting loss of this kinase affects one or more stages of Toxoplasma lytic cycle. Since TgTKL4 is a cell-cycle regulated kinase and parasites deficient in this enzyme show abnormal shape, we hypothesize that this kinase is a part of the signaling network that dictates parasite morphology during endodyogeny. To further understand the role of this novel TKL kinase in parasite replication, we propose to: (1) Identify substrates of TgTKL4; and (2) Determine the role of TgTKL4 in Toxoplasma endodyogeny. Thus, our proposed work will help us understand the precise function of TgTKL4 and signaling network associated with this kinase during cell division that determines parasite morphology.

项目总结/摘要弓形虫是一种重要的人类病原体，以独特的细胞分裂方式进行分裂称为内分裂，与哺乳动物细胞中发生的二分裂截然不同。以来弓形虫的分裂与高等真核生物不同，为了更好地理解这种复杂性，过程和确定其关键组成部分及其监管模式，为选择性策略阻断感染打开了大门。TgTKL 4是酪氨酸激酶的成员弓形虫中定位于寄生虫细胞质的TKL家族蛋白及其表达主要局限于细胞周期的合成（S）、有丝分裂/胞质分裂（M/C）期。有趣的是，这种激酶的缺失导致细胞分裂缺陷，导致畸形的寄生虫，适应性降低，毒力减弱。具体地，具有异常的TgTKL 4无效突变体，形态显示出显着的缺陷，在体外繁殖表明这种激酶的损失影响弓形虫溶解周期的一个或多个阶段。由于TgTKL 4是细胞周期调节激酶，缺乏这种酶的寄生虫表现出异常的形状，我们假设这种激酶是一部分，决定内分泌期寄生虫形态的信号网络。进一步为了了解这种新型TKL激酶在寄生虫复制中的作用，我们建议：（1）鉴定 TgTKL 4的底物;（2）确定TgTKL 4在弓形虫内皮炎中的作用。因此，在本发明中，我们的工作将有助于我们理解TgTKL 4和信令网络的确切功能在细胞分裂过程中与这种激酶相关，决定寄生虫的形态。