Mapping the directionality of forces generated by T. gondii tachyzoites moving in 3D

绘制弓形虫速殖子在 3D 中移动时产生的力的方向性

• 批准号: 9510443
• 负责人: GARY E WARD
• 金额: $ 22.01万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-14 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9510443
• 关键词: Acute; Affect; American; Area; Biological; Biology; Biophysics; Cells; Cellular biology; Collaborations; Complex; Data; Development; Disease; Drug Targeting; Environment; Eukaryotic Cell; Extracellular Matrix; Fetal Development; Future; Goals; Human; Image Analysis; Immunocompromised Host; Impairment; Individual; Infection; Invaded; Investigation; Life; Life Cycle Stages; Maps; Methods; Modeling; Monitor; Motor; Movement; Myosin ATPase; Parasites; Pathogenesis; Pattern; Play; Population; Pregnancy; Prevention approach; Process; Proteins; Resolution; Role; Shapes; Speed; Structure; System; Technology; Testing; Text; Three-Dimensional Imaging; Time; Tissues; Toxoplasma gondii; Toxoplasmosis; Traction; Virulence; Work; base; cell motility; disorder prevention; experience; extracellular; innovation; insight; mathematical model; member; neonate; novel strategies; pathogen; spatiotemporal; three-dimensional modeling; tool

Toxoplasma gondii is a widespread apicomplexan parasite that causes life-threatening disease in neonates and immunocompromised individuals. T. gondii and other apicomplexan parasites use a unique form of gliding motility to invade into and escape from cells of their hosts and to disseminate throughout the body during infection. It is well established that T. gondii MyosinA (TgMyoA) plays an important role in parasite motility, and parasites lacking TgMyoA are completely avirulent. How TgMyoA and the proteins with which it interacts work together to drive motility is therefore a fundamentally important question. Recent data have called into question the current “linear motor” model of motility and suggested the existence of a parallel, non- TgMyoA-based motility mechanism. This project will fill in a key gap in our understanding of parasite motility by determining the directionality of the forces generated by a parasite as it moves through the extracellular matrix. Capitalizing on our experience in high-speed imaging and analysis of parasite 3D motility and on our longstanding collaboration with mathematician Mark Rould, the Specific Aims of the project are to: (1) Develop 3D matrix deformation mapping methods to visualize the directionality of the forces moving parasites exert on the surrounding extracellular matrix and (2) Use 3D matrix deformation mapping to test key predictions of the linear motor model of T. gondii motility and to determine how disruption of the motor machinery affects the ability of the parasite to generate force. Motility plays a central role in the life cycle and virulence of T. gondii, yet the underlying mechanisms remain controversial. Understanding how the parasite generates force and determining whether it can use alternative mechanisms in the absence of TgMyoA will be critical to developing new, effective drugs that target parasite motility. The innovative methods developed here will be used to test key tenets of the current model of parasite motility, bring clarity to the role of TgMyoA and enable new approaches to analyzing motility based on the parasite's ability to generate force. Since the proteins and mechanisms underlying motility appear to be conserved among apicomplexans, the new mechanistic insights generated by this study and the future work it enables are likely to be directly relevant not just to T. gondii, but to other apicomplexan parasites as well. .

刚地弓形虫是一种广泛分布的顶复门寄生虫， 新生儿和免疫受损个体。t.弓形虫和其他顶复门寄生虫使用一种独特的形式 具有滑动运动性，侵入并逃离宿主细胞，并扩散到全身 在感染期间。T.弓形虫肌球蛋白A（TgMyoA）在寄生虫中起重要作用 缺乏TgMyoA的寄生虫是完全无毒的。TgMyoA及其蛋白质是如何 因此，相互作用共同驱动运动性是一个根本性的重要问题。最近的数据 质疑目前的"线性电机"模型的运动，并建议存在一个平行的，非- 基于TgMyoA的运动机制。 这个项目将填补一个关键的差距，我们的理解寄生虫运动，确定方向性 寄生虫在细胞外基质中移动时产生的力。利用我们 在寄生虫3D运动的高速成像和分析方面的经验以及我们长期的合作 与数学家Mark Roud合作，该项目的具体目标是：（1）开发3D矩阵变形 映射方法，以可视化移动寄生虫对周围环境施加的力的方向性 细胞外基质和（2）使用3D矩阵变形映射来测试线性电机的关键预测 模型T.弓形虫运动，并确定如何破坏的运动机制影响的能力， 寄生虫来产生力量 运动性在T.弓形虫，但潜在的机制， 仍然存在争议。了解寄生虫如何产生力，并确定它是否可以使用 缺乏TgMyoA的替代机制对于开发新的有效药物至关重要， 寄生虫能动性这里开发的创新方法将用于测试当前模型的关键原则， 寄生虫运动性，使TgMyoA的作用变得清晰，并使新的方法能够基于 寄生虫产生力量的能力由于运动的蛋白质和机制似乎是 保守之间apicomplexans，新的机制的见解产生的这项研究和未来的工作， 使能可能不仅与T直接相关。弓形虫，但对其他顶复门寄生虫也是如此。 .