The candidate is an assistant professor of Anesthesiology and Physiology. In the past, he has studied the pharmacology of synaptic transmission in sensory pathways using patch- and micropipette intracellular and extracellular recording methods. He now proposes to supplement his expertise in electrophysiologic methods with knowledge of the methods of molecular medicine under the mentorship of an expert in the genetics, structure, function and regulation of voltage-gated Na+ channels. This additional training will enable him to independently pursue his long-term goal of studying the physiology of sensory systems with a focus on mechanisms of importance to the anesthesiologist. The institutional environment at this premier center of molecular medicine, neuroscience and anesthesiology is highly conducive to the candidate's training and pursuit of his long-term goal. Interdisciplinary collaboration is encouraged and all facilities and resources necessary for the proposed training are available. The vehicle for the candidate s training is a study of the pattern of expression of voltage-gated Na+ channel alpha-subunit isoforms in nociceptors and other peripheral neurons. Nociceptor-specific modulation of voltage-gated Na+ channel function would represent a dramatic improvement over current use of local anesthetics in the treatment of perioperative, obstetric and chronic pain. Thus, the candidate proposes to directly test the hypothesis that nociceptors differ from other peripheral neurons in their expression of alpha-subunit isoforms. Single, dissociated nociceptors and other peripheral neurons will be characterized by pre- dispersal labeling with dye transported from the target of innervation, size, capsaicin-responsiveness and the biophysical behavior and TTX- sensitivity of their Na+ currents. The cytoplasm of characterized neurons will be harvested to detect the presence of transcripts of all known alpha-subunit genes. These results will identify those alpha- subunit isoforms that are selectively expressed on nociceptors, and hence, are potential targets for nociceptor-specific block. The candidate will also create cell lines expressing individual alpha- subunit genes for detailed physiologic and pharmacological characterization. These cell lines will be the cornerstone of future efforts to develop isoform-specific modulators of Na+ channel function.
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