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.
The ability to sense force is critical for myriad functions in the body, yet the molecular mechanisms of force-sensing are the least understood among all sensory systems. We identified the mechanically-activated Piezo2 ion channel, and showed that it plays a critical role in detecting touch, proprioception and lung stretch, but not noxious mechanical stimuli. In this proposal, we describe approaches we will take to explore the roles of Piezo2 in various forms of internal-organ mechanotransduction and to identify the elusive receptors involved in mechanical pain.
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