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SUMMARY OF THE PROJECT 164/2007

TITLE: PERIPHERAL MECHANISMS OF INFLAMMATORY PAIN: THE ROLE OF ION CHANNELS ACTIVATED BY EXTREME TEMPERATURES, TRPA1 AND TRPV2

DIRECTOR : PROF. DR. ALEXANDRU BABES

OF THE SIX TEMPERATURE-GATED ION CHANNELS FROM THE TRP (TRANSIENT RECEPTOR POTENTIAL) FAMILY, THE LEAST IS KNOWN ABOUT TRPV2 AND TRPA1. EXPRESSED IN A VARIETY OF NEURONAL AND NON-NEURONAL TISSUES, TRPV2 IS A HIGH-THRESHOLD (>52 ºC) HEAT RECEPTOR-CHANNEL, PROPOSED TO ACT AS A SENSOR FOR INTENSE NOXIOUS HEAT IN MAMMALIAN SENSORY NEURONS. AT THE OTHER END OF THE TEMPERATURE SPECTRUM, TRPA1 IS ACTIVATED BY NOXIOUS COLD (<17 ºC) AND BY PUNGENT COMPOUNDS, SUCH AS ALLYL ISOTHIOCYANATE, ALLYCIN AND CINNAMON ALDEHYDE (THE ACTIVE COMPOUNDS IN MUSTARD, GARLIC AND CINNAMON, RESPECTIVELY). IN MAMMALS, TRPA1 IS HIGHLY EXPRESSED IN SENSORY NEURONS FROM DORSAL ROOT (DRG) AND TRIGEMINAL (TG) GANGLIA AND ALSO IN THE INNER EAR. THE AIM OF THIS PROJECT IS TO COMBINE A VARIETY OF ELECTROPHYSIOLOGICAL AND MOLECULAR BIOLOGY TECHNIQUES IN ORDER TO CLARIFY THE INVOLVEMENT OF TRPV2 AND TRPA1 IN ACUTE PAIN AND IN THE DEVELOPMENT OF THERMAL HYPERSENSITIVITY IN INFLAMMATION. FIRST, WE INTEND TO FUNCTIONALLY EXPRESS TRPV2 AND TRPA1 IN A MAMMALIAN EXPRESSION SYSTEM AND TO CARRY OUT A DETAILED KINETIC AND PHARMACOLOGICAL CHARACTERIZATION OF THE RESPONSE OF THESE TWO CHANNELS TO THERMAL AND CHEMICAL STIMULI, USING CALCIUM MICROFLUORIMETRY AND THE PATCH-CLAMP TECHNIQUE. SECOND, WE SHALL USE THE MODEL OF DRG NEURONS IN PRIMARY CULTURE TO INVESTIGATE THE FUNCTIONAL FEATURES AND THE MODULATION OF NATIVE TRPV2 AND TRPA1. THIRD, USING SINGLE-CELL RT-PCR, WE SHALL BE ABLE TO IDENTIFY THE PRESENCE OF THE MRNA FOR THE TWO CHANNELS IN FUNCTIONALLY CHARACTERIZED DRG NEURONS. FINALLY, THE RELEVANCE OF THE RESULTS OBTAINED USING THE EXPRESSED TRPV2 AND TRPA1 AND THE DRG SOMA IN CULTURE WILL BE VALIDATED BY RECORDING TRPV2- AND TRPA1-MEDIATED ACTIVITY IN INTACT NERVE ENDINGS IN AN IN VITRO SKIN-NERVE PREPARATION FROM RAT AND MOUSE. WE FIRMLY BELIEVE THAT THE OUTCOME OF THIS PROJECT WILL LEAD TO A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING ACUTE PAIN AND HYPERSENSITIVITY TO THERMAL STIMULI IN INFLAMMATION.

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