The Mechanics of Piezo Ion Channels

非技术概述追溯到古代，人们已经认识到触摸，即感知机械刺激的能力，是生活的基础。然而，长期以来，人类和其他脊椎动物机械感觉的分子机制一直难以捉摸。最近发现，压电离子通道为一系列看似无关的机械感觉提供了分子基础。这为发现和描述脊椎动物机械感觉的一般物理机制和原理提供了一个独特的机会。这个项目的主要研究目标是构思一个描述压电离子通道的机械和机械激活的物理理论。由该项目支持的研究小组与实验小组密切合作，测试和提炼这一压电力学理论，目的是阐明脊椎动物机械传感的物理基础。这个项目的研究部分是基于这样一种前景，即对机械感觉背后的物理原理的定量理解将产生对生命的新的基本见解，并且对机械感觉的物理理解也将为在正常生理条件下和在疾病条件下(例如在慢性疼痛的情况下)对机械感觉进行定量分析和控制提出新的方法。该项目支持的跨学科研究将与高中、本科和研究生教育中物理和生物相结合的跨学科教学活动紧密结合起来。技术概述脊椎动物和其他生物一样，拥有对机械刺激做出反应的各种感觉。尽管进行了激烈的努力，但脊椎动物机械感觉的分子和物理机制长期以来一直难以捉摸。2010年，一类以前未知的机械敏感离子通道Piezo蛋白被发现，这导致了在阐明脊椎动物机械感觉的分子基础方面取得了惊人的进展。已发现Piezo在脊椎动物许多重要的生理功能中起着机械感觉的作用，如心血管机械转导、上皮细胞稳态的机械感觉、本体感觉、触摸感觉和呼吸系统的机械转导。目前已有几种Piezo的分子结构，这为定量地、物理地理解Piezo如何与周围的膜相互作用来感觉机械刺激提供了独特的机会。基于凝聚态理论和材料科学的方法，本项目旨在发展描述Piezo离子通道机制的物理理论，从而阐明细胞膜中Piezo门控的物理基础：(1)开发描述Piezo门控和Piezo局部化与局部膜组成、膜形状和对膜施加的力的依赖的物理模型；(2)探索Piezo如何通过膜与其他蛋白质相互作用，以及这如何引起Piezo的协同门控反应；以及(3)开发描述观察到的Piezo泡的形状和能量的物理模型，并在此基础上探索Piezo的蛋白质机制。通过该项目开发的压电力学的物理理论直接受到实验的推动，由该项目支持的研究团队与实验小组密切合作，测试和提炼新的膜-压电相互作用模型。鉴于Piezo在脊椎动物机械传感中的无处不在，该项目提出了一个令人兴奋的前景，即简单的物理机制和原理支撑着一系列复杂的生理功能，这可能揭示看似无关的生物现象之间新的和意想不到的联系。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Nontechnical summaryGoing back to antiquity, it has been recognized that touch, the ability to sense mechanical stimuli, is fundamental to life. However, the molecular mechanisms underlying mechanosensation in humans and other vertebrates have long remained elusive. Piezo ion channels have recently been found to provide the molecular basis for a wide range of seemingly unrelated forms of mechanosensation. This presents a unique opportunity to discover and describe general physical mechanisms and principles underlying vertebrate mechanosensation.The primary research objective of this project is to conceive a physical theory describing the mechanics, and mechanical activation, of Piezo ion channels. The research team supported by this project works closely with experimental groups to test and refine this theory of Piezo mechanics, with the aim of elucidating the physical basis for mechanosensation in vertebrates. The research component of this project is motivated by the prospect that a quantitative understanding of the physical principles underlying mechanosensation will yield new fundamental insights into life, and that a physical understanding of mechanosensation will also suggest novel approaches for the quantitative analysis and control of mechanosensation under normal physiological conditions and under disease conditions, such as in the case of chronic pain. The interdisciplinary research supported by this project will be closely integrated with interdisciplinary teaching activities at the interface of physics and biology, at the level of high school, undergraduate, and graduate education.Technical summaryIn common with other organisms, vertebrates possess a variety of senses that respond to mechanical stimuli. Despite intense efforts, the molecules and physical mechanisms responsible for vertebrate mechanosensation have long remained elusive. In 2010, Piezo proteins, a previously unknown class of mechanosensitive ion channels, were discovered, which has led to stunning progress in the elucidation of the molecular basis for vertebrate mechanosensation. Piezo has been found to underlie mechanosensation in many important physiological functions in vertebrates, such as cardiovascular mechanotransduction, mechanosensing in epithelial homeostasis, proprioception, sensing of touch, and mechanotransduction in the respiratory system.Several molecular structures of Piezo are now available, which presents a unique opportunity to arrive at a quantitative, physical understanding of how Piezo interacts with the surrounding membrane to sense mechanical stimuli. Based on approaches from condensed-matter theory and materials science, this project aims to develop a physical theory describing the mechanics of Piezo ion channels, and thus to elucidate the physical basis for Piezo gating in cell membranes: the project (1) develops physical models describing the dependence of Piezo gating and Piezo localization on local membrane composition, membrane shape, and force exertion on the membrane; (2) explores how Piezo interacts through the membrane with other proteins, and how this might give rise to cooperative gating responses of Piezo; and (3) develops physical models describing the shape and energetics of the observed Piezo vesicles and, on this basis, explores the protein mechanics of Piezo. The physical theory of Piezo mechanics developed through this project is directly motivated by experiments, and the research team supported by this project works closely with experimental groups to test and refine new models of membrane-Piezo interactions. Given the ubiquity of Piezo in vertebrate mechanosensation, this project raises the exciting prospect that simple physical mechanisms and principles underlie a diverse array of complex physiological functions, which may reveal new and unexpected links between seemingly unrelated biological phenomena.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.