Collaborative Research: Mathematical, Numerical, and Experimental Investigation of Flow Sensing by the Primary Cilium

合作研究：初级纤毛流量传感的数学、数值和实验研究

• 批准号: 1951526
• 负责人: Zhangli Peng
• 金额: $ 15万
• 依托单位: University of Illinois at Chicago
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1951526&HistoricalAwards=false
• 关键词: Collaborative; Research; Mathematical; Numerical; Experimental

This interdisciplinary team of three investigators will integrate mathematical modeling, numerical simulations, and experiments to investigate key fundamental issues surrounding the mechanosensory roles of primary cilia. Primary cilia are solitary (one per cell), immotile, antenna-like microtubule-based organelles extending from the surface of nearly every mammalian cell. Mechanical stimuli (such as blood flow) cause deflection of the primary cilium, initiating downstream signaling cascades to the rest of the cell. Defects in primary cilia have been associated with atherosclerosis, osteoporosis, and cancer. Yet the biochemical signaling pathways from primary cilia bending to cellular responses remain a complex and unsolved problem that will be addressed by the three PIs. Results from the proposed research will further our understanding of subcellular mechanosensing of primary cilia, and will lay the foundation for designing therapeutic strategies to treat various human diseases due to defected primary cilia. The PIs will engage both undergraduate and graduate students to conduct interdisciplinary research, and results from the proposed research can provide new approaches in mathematical biology, biophysics, biomedical engineering and medicine. The methods and techniques to be developed in this project will go beyond the context of primary cilia and extend to other problems featuring mechanically induced cellular functions, for example, in the regulation of vascular tone. Long speculated to trigger intracellular calcium release as a second messenger for subsequent cellular biochemical signaling and responses (such as change in patterns of cytoskeleton or altered ion and solvent transport), recent experiments using genetically-coded calcium indicators refuted the calcium-responsiveness of primary cilia for a range of cells. Thus it is imperative to establish fundamental understanding of the role of primary cilia in subcellular mechanosensing. One main challenge to identify the pathway(s) from cilium bending to subsequent bio-chemical signaling is to isolate primary cilium contribution from the rest of the cell responding directly to the same mechanical stimuli. By using an optical trap, PI Resnick is able to bend a single primary cilium without exerting force on the rest of the cell, thus providing a great opportunity for insight to the missing pathways. Combining this experimental technique with mathematical modeling (PI Young) and numerical simulations (PI Peng), the team aims to (1) characterize the mechanical properties of the primary cilium, (2) qualify the coupling between cilium and cytoskeleton, and (3) identify the time scales and characteristics of signaling activation to quantify ciliary-mediated flow sensing. Results from these three aims will advance the mathematical modeling of the primary cilium and how it couples to the intracellular signaling pathways. This award is co-funded with the Cellular Dynamics and Function program in Division of Molecular and Cellular Biosciences, and the Life Science Venture Fund in DMS.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.

这个由三名研究人员组成的跨学科团队将整合数学建模，数值模拟和实验，以研究围绕初级纤毛的机械感觉作用的关键基本问题。初级纤毛是孤立的（每个细胞一个），不动的，基于微管的触角状细胞器，从几乎每个哺乳动物细胞的表面延伸。机械刺激（如血流）引起初级纤毛偏转，启动下游信号级联到细胞的其余部分。初级纤毛的缺陷与动脉粥样硬化、骨质疏松症和癌症有关。然而，从初级纤毛弯曲到细胞反应的生化信号通路仍然是一个复杂且未解决的问题，将由三个PI解决。这项研究的结果将进一步加深我们对初级纤毛的亚细胞机械传感的理解，并为设计治疗策略以治疗由初级纤毛缺陷引起的各种人类疾病奠定基础。PI将吸引本科生和研究生进行跨学科研究，拟议研究的结果可以为数学生物学，生物物理学，生物医学工程和医学提供新的方法。在这个项目中开发的方法和技术将超越初级纤毛的背景，并扩展到机械诱导的细胞功能的其他问题，例如，在血管张力的调节。长期推测触发细胞内钙释放作为随后的细胞生化信号和反应（如细胞骨架模式的变化或改变离子和溶剂运输）的第二信使，最近的实验使用遗传编码的钙指标反驳了一系列细胞的初级纤毛的钙反应。因此，必须建立初级纤毛在亚细胞机械传感中的作用的基本理解。鉴定从纤毛弯曲到随后的生化信号传导的途径的一个主要挑战是将主要纤毛贡献与直接响应相同机械刺激的细胞的其余部分分离。通过使用光阱，PI Resnick能够弯曲单个初级纤毛，而无需对细胞的其余部分施加力，从而为深入了解缺失的途径提供了绝佳的机会。将这种实验技术与数学建模（PI Young）和数值模拟（PI Peng）相结合，该团队的目标是（1）表征初级纤毛的机械特性，（2）鉴定纤毛和细胞骨架之间的耦合，（3）确定信号激活的时间尺度和特征，以量化纤毛介导的流量传感。这三个目标的结果将推进初级纤毛的数学建模，以及它如何耦合到细胞内信号通路。该奖项由分子和细胞生物科学部的细胞动力学和功能项目以及DMS的生命科学风险基金共同资助。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。