PROJECT SUMMARY Touch is essential for our survival and for social bonding, and in disrupted in many forms of injuries and disease states. Despite its fundamental importance, touch transduction remains one of the least understood signaling processes, both at the cellular and molecular levels. Touch is mediated by receptors imbedded in the skin, most of which are composed of nerve endings and accessory glial or epithelial cells. Groundbreaking work on the mammalian Merkel cells complex demonstrated that the epithelial cell, rather than the neuron, is the primary sensory cell. However, little is known about the contribution of glia to the function of other touch receptors, including the Pacinian and Meissner’s corpuscles. If glia of touch receptors are found to sense and mediate the transduction of mechanical forces, this finding would constitute a paradigm shift and may suggest these cells as novel targets for the treatment of conditions in which touch is disrupted. My lab has dedicated the last 16 years to the study of glia/neuron cross talk using the pioneering model organism C. elegans. We found that Amphid glial cells (Amsh) of the worm nose touch receptor complex respond to touch by rise of intracellular Ca2+ and Cl-. These results suggest that Amsh glia may be endowed with mechanisms that detect mechanical forces. Furthermore, we found that Ca2+ responses in Amsh glia temporally precede neuronal Ca2+ responses, raising the intriguing possibility that glia might be the primary sensory cells. The goal of this proposal is to leverage C. elegans genetics, in vivo Ca2+ and Cl- imaging tools, and straightforward behavioral assays to dissect from gene to behavior glial mechanosensitivity and glia/neuron cross talk in the worm nose touch receptor. Our inter-related but independent aims are: 1) To determine what mediates Ca2+ transients in Amsh glia upon touch stimulation and their function in touch, 2) To identify mechanisms of glia/neuron crosstalk in touch receptors, and 3) To determine what mediates Amsh glial Cl- changes upon touch stimulation and their function in touch. Pioneering work in mammals has advanced our understanding of touch sensation. However, progress has been hindered by the difficulty of harvesting touch receptors from the skin and the complexity of the mammalian system. I have now the unprecedented opportunity to capitalize on this previous work to explore a new area in the field using the genetically amenable and more tractable model C. elegans. My work is likely to reveal general principles of glial function and glia/neuron crosstalk relevant to other sensory systems and other parts of the nervous system.