Research Report 2010 - MDC

Current ResearchI remain fascinated by mechanistic aspects of sensoryneuroscience and my research team will continue tofocus on understanding sensory mechanisms at themolecular level. We are investigating 3 areas in thisfield:Identification of sensory TRP channel modulators.By analogy to TRP channels in the Drosophila eye, wehypothesize that the mammalian orthologs are componentsof supramolecular membrane-bound proteincomplexes that enable the channels to function specificallyand effectively in a context dependent manner.We are using genetic, biochemical and functionalscreening paradigms to identify components of thisputative modulatory complex.Identification of molecules involved in developmentaland functional aspects of mechanosensation.The ability of cells to detect and transduce mechanicalstimuli is a fundamental biological process that underliestouch, pain and control of muscle tension. In vertebrates,a subpopulation of somatosensory neurons isspecialized to detect these different mechanical stimulibut how they accomplish this task is at present notunderstood. Similarly, the developmental program thatallows these neurons to differentiate into a diversity ofcell types with very specific mechanosensitive traits islargely unknown.We are employing a multidisciplinary approach gearedtowards the identification and characterization of moleculesthat are necessary for the development andfunction of mechanosensory neurons. Using the mouseas a model system, we have conducted a genetic screenthat will allow us to isolate molecules such as transcriptionfactors and signaling molecules involved inthe differentiation of mechanosensory neurons.Subsequently, we will test their potential to drive differentiationof neuronal precursors into specific mechanosensoryneurons using stem cell biology.Molecular mechanisms underlying temperaturedetectionand core body temperature regulation.Temperature detection and regulation is of vital importanceto any homeothermic organism. In order to maintaintemperature homeostasis it is necessary for theautonomic nervous system to monitor small fluctuationsin core body temperature and initiate counterThe picture depicts Embryonic Stem (ES-) cells that have been differentiatedinto neuronal precursors in vitro. The cells have been stainedwith antibodies for the neurofilament nestin (red), the cell proliferationmarker Ki-67 (green). The cell nuclei are labeled by Dapi (blue).Our goal is to differentiate these precursors into sensory neuron lineages,thereby generating largely homogenous cell populations thatcan be used for biochemical experimentation.measures to prevent temperature fluctuations beyonda tightly controlled set point. Key brain centers concernedwith temperature control are the preoptic areaand anterior hypothalamus (PO/AH). These hypothalamicregions harbor neurons that not only detectchanges in core body temperature, but are also believedto receive and integrate input from ascendingsomatosensory pathways carrying information fromperipheral temperature sensors.The molecular machinery underlying central temperaturedetection by hypothalamic neurons is currentlyunknown. We will characterize the thermal responseproperties generated by hypothalamic PO/AH neurons,with the goal of elucidating mechanisms underlyingtheir temperature sensitivity.Selected PublicationsSiemens, J, Zhou, S, Piskorowski, R, Nikai, T, Lumpkin, EA, Basbaum, AI, King,D, Julius, D. (2006). Spider Toxins activate the Capsaicin Receptor toproduce Inflammatory Pain. Nature. 444, 208-212.Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL,Jordt SE, Julius D. (2007). The Menthol Receptor TRPM8 is the PrincipalDetector of Environmental Cold. Nature. 448, 204-208.Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B,Imamachi N, Andrè E, Patacchini R, Cottrell GS, Gatti R, Basbaum AI,Bunnett NW, Julius D, Geppetti P. (2007). 4-Hydroxynonenal, anEndogenous Aldehyde, causes Pain and Neurogenic Inflammationthrough Activation of the Irritant Receptor, TRPA1. Proc Natl Acad Sci. 104,13519-24.Function and Dysfunction of the Nervous System 173