We do not know the molecular identities of the receptors that allow us to hear, feel touch, or taste sour and salt. These senses rely on ion channels that open directly in response to a physical stimulus, but for most of them, the specific receptor molecules remain unknown. This project will identify those missing receptors by exploiting the genetic tools of the roundworm *C. elegans*. The researchers will first characterise a family of candidate receptors called TMC proteins, which have been linked to hearing and taste in mammals. They will insert mouse and worm TMC genes into worm neurons to study how the proteins respond to stimuli, then test the same proteins in knockout mice to confirm their roles in a living mammal. Separately, they will screen thousands of worm mutants for defects in sensory behaviour, aiming to discover entirely new families of ionotropic receptors that may be conserved in humans. This is fundamental science. It will fill a basic gap in sensory biology—identifying the molecules that detect sound, pressure, and specific tastants. If successful, it could eventually inform treatments for hearing loss or taste disorders, but the immediate value is a mechanistic understanding of how our bodies sense the physical world.
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Despite many years of study, the molecular mechanisms underlying several humansenses, in particular hearing, touch, and sour and salt taste, remain poorly understood. Each of these processes relies on ionotropic receptors that are directly gated by the sensory stimulus; however, the mechanisms underlying this gating, and in many cases even the identities of the the relevant receptor molecules, remain unknown. Recently, work from our lab and others has implicated members of the TMC family of putative ion channels as sensory receptors for taste and hearing[1,2]. In the planned research, we will characterize the in vivo roles and functional properties of worm and mammalianTMCs and determine how they respond to sensory stimuli. Since mammalian sensory receptors often retain functionality when heterologously expressed across phyla[2,3], we will use the genetic tractability of C. elegans to dissect functional domains of mouse and worm TMCs in an in vivo context. In addition, since known families of ionotropic sensory receptors are largely conserved in the worm[4], we expect that novel receptors with conserved roles in mammals can identified by worm genetics. We will therefore screen for novel ionotropic sensory receptors by highthroughput phenotyping of C. elegans mutants. Specific aims include: 1. Characterize the functional properties of mammalian and worm TMC proteins by heterologous expression in C. elegans neurons. 2. Investigate the relationship between TMC protein structure and function through analysis of chimeras and mutant proteins. 3. Using the information from heterologous expression studies, study the in vivo functions of mouse TMCs in knockout animals. 4. Identify novel sensory receptors by high-throughput phenotyping of C. elegans knockout strains.
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