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，包括听觉、体感和内感受等多种过程。尽管它们的生理重要性，机械转导通道的分子身份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，Piezo 1和Piezo 2，并表明Piezo 2在检测触摸，本体感觉和肺拉伸，但不是有害的机械刺激中起着关键作用。然而，大问题仍然存在：还有哪些机械感觉系统依赖于Piezos，以及剩余的有害机械感觉器的身份是什么？我们将探索Piezo 2在各种形式的内部器官机械传导（内感受）中的作用，包括饱腹感和压力感受-对正常生理学和病理生理学至关重要的过程。除了Piezo 2之外，未知的机械传感器介导导致疼痛感知的有害机械力的转导，并且预计是重要的治疗靶点。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Piezo 2对触摸所做的那样。

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.