Internal temperature homeostasis is of critical importance to our health as deviation from a normal, tightly controlled level (37 °Celsius) can cause fatal organ failures. Temperature-sensitive cells in the hypothalamus detect deep brain temperature, which is directly relevant to core body temperature (CBT) regulation. However molecules and mechanisms underlying central temperature detection by hypothalamic neurons are unknown. I propose to use a multi-disciplinary approach to elucidate mechanisms of temperature detection by these cells. I have started to employ a genetic tagging approach that allows me to label temperature-activated hypothalamic neurons in vivo.Hypothalamic neurons not only detect local brain temperature but also receive peripheral temperature signals from the somatosensory system. However, the impact of peripheral temperature information on central temperature regulation is largely unknown. Transient Receptor Potential (TRP) ion channels have been found to constitute important components in a variety of different sensory systems. In vertebrates, TRP family members TRPV1, TRPM8, and TRPA1, play prominent roles in the detection of thermal stimuli ranging from cold to hot ambient temperatures. How these receptors mediate their temperature sensitivity on the molecular level is largely unknown. I hypothesize that TRPs are components of supramolecular membrane-bound protein complexes that enable the receptors to function in a context-dependent manner, similar to the founding member of the TRP receptor family in the Drosophila eye. I will use a genetic biochemical strategy to identify components of somatosensory TRP channel protein complexes from native sensory ganglia of transgenic mice. Subsequently, characterization of the TRP Proteome will not only provide novel insights into TRP channel function as temperature sensors but may additionally yield novel targets for the treatment of inflammatory conditions and pain.