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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
5R35NS105067-02
Application #
9612582
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Silberberg, Shai D
Project Start
2017-12-15
Project End
2025-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Jojoa-Cruz, Sebastian; Saotome, Kei; Murthy, Swetha E et al. (2018) Cryo-EM structure of the mechanically activated ion channel OSCA1.2. Elife 7:
Murthy, Swetha E; Dubin, Adrienne E; Whitwam, Tess et al. (2018) OSCA/TMEM63 are an Evolutionarily Conserved Family of Mechanically Activated Ion Channels. Elife 7:
Zeng, Wei-Zheng; Marshall, Kara L; Min, Soohong et al. (2018) PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science 362:464-467