Mechanisms of force sensing in the nervous system

与视觉、味觉和嗅觉不同，机械感觉超越了单一的感觉器官，并包括听觉、体感和内感受等多种过程。尽管它们具有重要的生理意义，但机械转导通道的分子特性在很大程度上是未知的。我们的实验室发现了第一个脊椎动物机械门控阳离子通道，Piezo1和Piezo2，并表明Piezo2在检测触摸，本体感觉和肺部拉伸中起关键作用，但不是有害的机械刺激。然而，大问题仍然存在：还有什么其他的机械感觉系统依赖于Piezos，剩下的有害机械传感器的身份是什么？我们将探讨Piezo2在各种形式的内部器官机械传导（内感受）中的作用，包括饱腹感和压力接受-对正常生理和病理生理至关重要的过程。除了Piezo2，未知的机械传感器介导了导致疼痛感知的有害机械力的转导，并有望成为重要的治疗靶点。我们将使用高通量筛选和功能基因组学方法来寻找这些受体。识别这些难以捉摸的传感器将打破疼痛领域，就像Piezo2对触觉所做的那样。

Unlike sight, taste and smell, mechanical senses extend beyond a single sensory organ, and encompass processes as diverse as hearing, somatosensation, and interoception. Despite their physiological importance, the molecular identity of mechanotransduction channels is largely unknown. Our lab discovered the first vertebrate mechanically-gated cation channels, Piezo1 and Piezo2, and have shown that Piezo2 plays a critical role in detecting touch, proprioception and lung stretch, but not noxious mechanical stimuli. However, big questions remain: what other mechanosensory systems depend on Piezos, and what is the identity of the remaining noxious mechanosensors? We will explore the role of Piezo2 in various forms of internal-organ mechanotransduction (interoception), including satiety and baroreception - processes crucial for normal physiology and pathophysiology. Beyond Piezo2, unknown mechanosensors mediate the transduction of noxious mechanical forces leading to the perception of pain, and are anticipated to be important therapeutic targets. We will use high-throughput screens and functional genomics approaches to find these receptors. Identifying these elusive sensors will break open the pain field, as Piezo2 has done for touch.