Novel molecular receptors in the sensory nervous system (360G-Wellcome-313078_Z_24_Z)

Mammals evolved complex physiological mechanisms to maintain temperature homeostasis and avoid harmful environmental temperature extremes. Sensory nerves detect external and internal temperatures via expression of differentially tuned molecular thermoreceptors. Many heat receptors have been identified in recent decades, with overlapping response intervals varying from moderate to damagingly hot temperatures. The remarkable redundancy of this system highlights its evolutionary importance. Though cold detection is also critical for survival, the molecular tools tuned to detect harmful temperature decreases are comparatively poorly understood. We employed a gain-of-function random mutagenesis technique coupled with a unique selection method to create and enrich cells that express novel cold receptors. We confirm de novo expression of at least one cold receptor within our cells that cannot be explained by any known sensory mechanism. We will investigate this, and other new receptors by studying their molecular properties, organism-wide expression patterns, and involvement in thermosensation, temperature homeostasis and metabolic control. Our work establishes a broadly applicable strategy for agonist-based receptor identification. Our long-term plans outline the use of this strategy to identify and characterise new high-value targets in the sensory nervous system and apply this technology as a target-screening tool as part of our commercialization efforts.