Spindle Self-Organization and Bioenergetics in Vivo

体内纺锤体自组织和生物能学

• 批准号: 2013874
• 负责人: Daniel Needleman
• 金额: $ 80万
• 依托单位: Harvard University
• 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: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2013874&HistoricalAwards=false
• 关键词: Spindle; Self; Organization; Bioenergetics; Vivo

There is no established framework capable of understanding the structure and behaviors of organelles, specialized structures within a cell that can contain millions of dynamic, energy-transducing molecules. Similarly, cellular metabolism is extremely complex, involving hundreds of proteins, intricate networks, and numerous intermediate metabolic compounds, and we currently lack the ability to predict the flux through different pathways. This project employs the paradigm used to study complex systems in physics of integrating quantitative experiments with phenomenological theories, but applies these methods to study the spindle, oocyte bioenergetics, and the interactions between the two. This work will provide fundamental insight into cell division and energy metabolism, and will help pave the way towards an understanding of the nonequilibrium thermodynamics of living matter. The goal of the project is to develop a quantitative understanding of the spindle, energy metabolism, and the interaction between the two. The knowledge gained will help explain how metabolic defects disrupt cell division and cytoskeletal organization, which is believed to cause diverse pathologies, including cancer, neurological diseases, and infertility. Furthermore, if the nonequilibrium thermodynamics of living, active matter become sufficiently well understood, it will eventually become possible to engineer manmade active materials with lifelike properties. Graduate students, undergraduates, and high school students will be trained in interdisciplinary research, both through working on the project, and in classes, summer courses, and tutorials. A strong effort will be taken to enhance the involvement of women and underrepresented minorities in these activities. The results obtained, will be disseminated in research journals, on the lab web site, and at conferences (including new, interdisciplinary conferences). The PI will create a monthly series of events on scientific communication that will help give graduate students and postdocs valuable skills and enhance their engagement with public outreach. These will include collaborations with high school teachers, writers, entrepreneurs and artists, and will help create a community of people who are passionate about scientific communication.Life is a nonequilibrium phenomenon. Metabolism provides a continuous flux of energy that dictates the form and function of many subcellular structures. These subcellular structures are active materials, composed of molecules which use chemical energy to perform mechanical work and locally violate detailed balance. One of the most dramatic examples of such a self-organizing structure is the spindle, which segregates chromosomes during cell division. Despite its central role, very little is known about the nonequilibrium thermodynamics of active subcellular matter, such as the spindle. In this project the PI will study the interplay between spindle behaviors and bioenergetics in mouse oocytes using a combination of quantitative experiments and theory. The goal of this project is to provide a systematic basis to understand and predict the behaviors of the spindle and energy metabolism in vivo, and how perturbing one impacts the other. This work also aims to contribute to physics through the quantitative study of the nonequilibrium thermodynamics of living, active matter.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.

目前还没有一个既定的框架能够理解细胞器的结构和行为，细胞器是细胞内可以包含数百万个动态能量转换分子的专门结构。同样，细胞代谢也非常复杂，涉及数百种蛋白质、错综复杂的网络和众多中间代谢化合物，我们目前缺乏预测不同途径通量的能力。本研究采用物理学中用于研究复杂系统的定量实验与唯象理论相结合的范式，但将这些方法应用于研究纺锤体，卵母细胞生物能量学以及两者之间的相互作用。这项工作将为细胞分裂和能量代谢提供基本的见解，并将有助于为理解生命物质的非平衡热力学铺平道路。该项目的目标是对纺锤体，能量代谢以及两者之间的相互作用进行定量了解。所获得的知识将有助于解释代谢缺陷如何破坏细胞分裂和细胞骨架组织，这被认为是导致不同的病理，包括癌症，神经系统疾病和不育症。此外，如果对生命活动物质的非平衡热力学有了充分的了解，最终将有可能设计出具有类似生命特性的人造活性材料。研究生、本科生和高中生将通过项目工作、课堂、暑期课程和辅导进行跨学科研究培训。将大力促进妇女和代表人数不足的少数群体参与这些活动。所获得的结果将在研究期刊、实验室网站和会议（包括新的跨学科会议）上传播。PI将创建一个关于科学传播的月度系列活动，这将有助于为研究生和博士后提供宝贵的技能，并加强他们与公众的接触。这将包括与高中教师、作家、企业家和艺术家的合作，并将有助于创建一个热衷于科学交流的社区。生命是一种非平衡现象。新陈代谢提供了一个连续的能量流，决定了许多亚细胞结构的形式和功能。这些亚细胞结构是活性材料，由分子组成，这些分子使用化学能来进行机械功，并局部破坏详细的平衡。这种自组织结构最引人注目的例子之一是纺锤体，它在细胞分裂过程中分离染色体。尽管它的核心作用，很少有人知道的非平衡热力学的活性亚细胞物质，如纺锤体。在这个项目中，PI将使用定量实验和理论相结合的方法研究小鼠卵母细胞纺锤体行为和生物能量学之间的相互作用。该项目的目标是提供一个系统的基础来理解和预测体内纺锤体和能量代谢的行为，以及扰动一个如何影响另一个。这项工作还旨在通过对活的、活性物质的非平衡热力学的定量研究为物理学做出贡献。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。