机械力感受行使触觉系统最为复杂精细的感知功能，它能使机体对各种机械力刺激作出反应以维持正常功能乃至存活。这一机制的异常可导致疼痛等疾病，严重影响个体健康与生活质量。机械力敏感非选择性阳离子通道被认为在机械力传感过程起着重要作用，但是这一通道在脊椎动物中的分子组成一直未被确定，极大的制约了我们对机械力感受分子细胞学机制的了解。本课题申请人之前的工作证实Piezo基因所编码的蛋白以多聚体形式组成一类约1.2 mega-Dalton、具120-160次跨膜区的全新离子通道，首次确证了脊椎动物中机械力敏感阳离子通道的分子组成。深入解析Piezo通道的结构功能关系及生理／病理学作用从而帮助理解机械力传感这一重要生物学机制具有非常重要的科学意义和创新性。我们将重点研究 Piezo通道在触觉／痛觉感受中的作用、解析其结构功能关系以揭示机械力敏感离子通道的作用规律和药理学价值。

Mechanosensation is one of the most complicated and sophisticated sensory modality of touch. It underlies our ability to sense variable forms of mechanical stimulation, which is critical for maintaining homeostasis and even survival. Sensitization of the system under tissue injury or inflammation can lead to mechanical hyperalgesia or allodynia. Despite its biological and clinical significance, the molecular and cellular mechanisms of mechanosensation are poorly understood. Mechanosensitive cation channels have long been postulated to play critical roles in mechanotransduction. However, their molecular identities and gating mechanisms in vertebrates had remained elusive. A major breakthrough has been made by the recent identification that the evolutionarily conserved Piezo gene family is essential in mediating mechanically activated cationic currents. My previous work show that mouse Piezo1 proteins by themselves assemble as ~1.2 mega-Dalton tetrameric complex with a distinct ~120-160 transmembrane segments, and purified Piezo1 reconstituted into lipid bilayers forms ion channels, establishing Piezo proteins as the first identified pore-forming subunits of mechanosensitive cation channels in vertebrates. The physiological roles and structure-function relationships of Piezo channels remain to be fully characterized. We have set up to elucidate their physiological roles in mechanosensation of touch and pain, and understand how they are gated by force and organized into three-dimensional complex, and search for specific chemical ligands as tool compounds and potential drug candidates. These studies will shed light on our understanding of the molecular and cellular mechanisms of mechanosensation and the working principle and pharmacological potential of mechanosensitive ion channels.

机械门控阳离子通道承担将机械力刺激转化为电化学信号的重要功能，参与触觉、痛觉、血压调节等基本生理活动。然而其在哺乳动物中的分子组成长期未被发现确证，阻碍了对其的深入理解。2010年，Piezo基因家族被发现编码哺乳动物机械门控阳离子通道的必要组成成分。2012年本项目负责人在从事博士后研究期间，首次证实Piezo蛋白编码哺乳动物机械门控阳离子通道的孔道蛋白，从而确立了机械门控Piezo通道这一全新通道家族 (Nature 2012。汤森路透1%高被引论文)。在本项目中，我们聚焦于揭示机械门控Piezo通道的结构功能关系这一关键科学问题，并取得了系列突破性研究成果：1）首次解析 了Piezo1通道的冷冻电镜三维结构，揭示其独特三聚体三叶螺旋桨状通道构造(Nature 2015)；2）鉴定发现了 Piezo通道负责离子通透与机械传感的分子基础，提出其以功能区模块化的方式行使机械门控离子通道功能的机制假说(Neuron 2016，2017)；3）鉴定发现了Piezo蛋白家族的新型调控蛋白SERCA，并系统阐明了其对Piezo蛋白通道活性调控的作用机制(Nature Communications，2017)。这些研究成果极大的推动了我们对机械门控Piezo通道分子作用机制与调控的理解。本申请人应邀在多个国际学术会议对相关研究成果进行口头报告，并应邀撰写有关Piezo通道结构功能机制的图书章节和综述（Current topics in Membranes 2017；Journal of Physiology 2017),体现了本申请人在该研究领域的国际性学术影响力。