The roles of TRPM8 in mechanotransduction and osmosensation. (360G-Wellcome-092648_Z_10_Z)

The mechanisms and the ion channels involved in mechanotransduction are poorly understood. Transient receptor potential (TRP) channels expressed in peripheral sensory nerves have been shown to play important roles in sensory transduction. The project is focussed on four related questions based on the hypotheses that the transient receptor potential (TRP) ion channel, TRPM8, plays a role in mechanotransduction and can act as a peripheral osmosensor in some peripheral sensory neurons. 1. Chang es in intracellular calcium concentration or membrane currents evoked by hyperosmotic and mechanical stimuli in identified DRG neurons and TRPM8 CHO cells will be used to determine if TRPM8 has a primary role in mechanotransduction. 2. Intrathecal administration of TRPM8 siRNA and pharmacological inhibition of TRPM8 with a novel antagonist will be used to determine if TRPM8 plays a role in the maintenance of neuropathic and inflammatory mechanical hypersensitivities. 3. Functional and protein /mRNA expression studies will determine if a change in TRPM8 expression contributes to increased mechanosensitivity in pathophysiological conditions. 4. Functional and immunocytochemical studies will reveal if TRPM8 is expressed in sensory neurons at key sites for peripheral osmosensation and is responsible for sensing changes in blood osmolarity in these regions.