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CAREER: Spatiotemporal organization of cytokinetic events

职业：细胞因子事件的时空组织

基本信息

批准号：
1941367
负责人：
Maitreyi Das
金额：
$ 127.33万
依托单位：
University of Tennessee Knoxville
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-01-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1941367&HistoricalAwards=false
关键词：
CAREER Spatiotemporal organization cytokinetic events

项目摘要

Cells employ multiple processes to grow and proliferate. Most cellular processes are highly complex, involving multiple steps that have to be precisely regulated both in time and within the correct region. Inability to organize these steps often leads to cell death. It is not clear how cells sense and signal these different steps during complex processes to ensure proper function. This project will investigate the complex multi-step process of cytokinesis, the final step in cell division. During cytokinesis, a series of steps ensures that a mother cell splits into two intact daughter cells. Using Schizosaccharomyces pombe, or fission yeast, as a model system, signaling patterns that organize different cytokinetic steps will be researched. Preliminary data show that different signaling proteins crosstalk to properly organize these steps. In this project the molecular mechanism of such a crosstalk and how it organizes cytokinetic steps will be investigated. The project will lead to an understanding of the principles that allow cells to sense and signal complex processes. These principles are applicable to higher organisms given that most of the signaling pathways investigated are highly conserved. This project will also involve the design of lab-based cell biology courses for high school and undergraduate students. The principal investigator, a high school science teacher, and a graduate student will be involved in developing the lab-based course. Graduate, undergraduate, and high school students will also be trained in conducting research. Students will be trained in experimental design, analysis and interpretation and their critical thinking capabilities will be honed. Under-represented undergraduate and high school students will participate in this project through the Educational Advancement Program and Upward Bound program respectively. All the trainees will be trained to present their research at national or international meetings.Cytokinesis, the final step in division, is a universal process in all eukaryotes in which a cell physically separates into two daughters after nuclear division. Successful completion of cytokinesis requires multiple steps that are sequentially coordinated. Disruption of the proper order of these steps can impair the genetic integrity of the progeny, lead to cell separation failure, or cause cell lysis. The goal of this project is to mechanistically define how different cytokinetic steps are spatiotemporally organized. Previous research showed the small GTPase Cdc42 to be required for initiation of septum formation during cytokinesis in fission yeast. Preliminary data show that Cdc42, crosstalk with other RHO GTPases, Rho1 and Rho4, to organize distinct cytokinetic events. Cdc42-Rho crosstalk has also been reported in wound healing, cell migration, and cell polarization. However, it is not known how crosstalk between different pathways coordinate multiple steps during cellular processes. This project will use cytokinesis as a paradigm to mechanistically define crosstalk between GTPases and explain how this enables coordination of complex multi-step processes. The project will involve interdisciplinary approaches with live cell 4D microscopy, molecular nano-traps, electron microscopy, and mathematical modeling. The project will also develop inquiry-driven cell biology lab courses to train future scientists in their quest to investigate the rules of life.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

细胞采用多个过程来生长和增殖。大多数细胞过程是高度复杂的，涉及多个步骤，必须在时间和正确的区域内精确调节。无法组织这些步骤通常会导致细胞死亡。目前尚不清楚细胞如何在复杂的过程中感知和发出这些不同步骤的信号，以确保正常的功能。本计画将探讨胞质分裂的复杂多步骤过程，胞质分裂是细胞分裂的最后一步。在胞质分裂期间，一系列步骤确保母细胞分裂成两个完整的子细胞。使用粟酒裂殖酵母或裂殖酵母作为模型系统，将研究组织不同细胞动力学步骤的信号模式。初步数据显示，不同的信号蛋白相互干扰，以正确组织这些步骤。在这个项目中，这样的串扰的分子机制，以及它如何组织细胞动力学步骤将被调查。该项目将导致对允许细胞感知和信号复杂过程的原理的理解。这些原则适用于高等生物，因为大多数研究的信号通路是高度保守的。该项目还将涉及为高中和本科生设计基于实验室的细胞生物学课程。主要研究者，一名高中科学教师和一名研究生将参与开发基于实验室的课程。研究生、本科生和高中生也将接受研究培训。学生将接受实验设计，分析和解释的培训，并培养他们的批判性思维能力。代表性不足的本科生和高中生将分别通过教育促进方案和向上拓展方案参加这一项目。所有学员将接受培训，在国家或国际会议上介绍他们的研究。胞质分裂是分裂的最后一步，是所有真核生物的一个普遍过程，细胞在核分裂后物理分离为两个子细胞。胞质分裂的成功完成需要顺序协调的多个步骤。这些步骤的正确顺序的破坏可损害后代的遗传完整性，导致细胞分离失败，或引起细胞裂解。这个项目的目标是机械地定义不同的细胞动力学步骤是如何时空组织的。先前的研究表明，小的GTdR Cdc 42是在分裂酵母胞质分裂期间启动隔膜形成所必需的。初步数据显示，Cdc 42与其他RHO GTP酶Rho 1和Rho 4串扰，以组织不同的细胞动力学事件。Cdc 42-Rho串扰也被报道在伤口愈合、细胞迁移和细胞极化中。然而，目前尚不清楚不同途径之间的串扰如何协调细胞过程中的多个步骤。这个项目将使用胞质分裂作为一个范例，机械地定义GTP酶之间的串扰，并解释这是如何使复杂的多步骤过程的协调。该项目将涉及活细胞4D显微镜，分子纳米陷阱，电子显微镜和数学建模的跨学科方法。该项目还将开发探究驱动的细胞生物学实验室课程，以培养未来的科学家，探索生命的规律。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。