Thomas V. Getchell - US grants

The long-term goal of the experiments described in this research proposal is to investigate the integrated physiological activity of chemosensory mucosae at the cellular, subcellular and molecular levels. Of particular interest is the role of secretory cells and their products, including glycosylated secretory glycoconjugates and the putative pheromone transporter vomeromodulin, in perireceptor events associated with chemosensory transduction. The specific aims to achieve this goal are: a: to study the extrinsic and intrinsic factors that regulate the developmental expression of vomeromodulin by the lateral nasal glands using molecular biological techniques including in situ hybridization and Northern blot analysis, and to compare the regulation with that of putative odorant transporter odorant binding protein; b. to determine the subcellular site of N-acetylglucosamine glycosylation of secretory glycoconjugates and to examine their distribution in electron-dense and - lucent mucoid domains of mucus and in the molecular ectodomains of the glycocalyx associated with olfactory cilia using lectinoprobes labeled with gold microspheres; c. to investigate the microstructure of the mucosensory compartments of the olfactory and vomeronasal mucosae with confocal laser scanning microscopy using lectinoprobes and antibodies labeled with fluorochromes; and d. to examine the developmental and odorant-regulated expression of Phase I and Phase II biotransformation enzymes, localized in sustentacular and secretory cells as well as mucosensory compartments, including cytochrome P450 NMa/b, glutathione S-transferases and gamma-glutamyl transpeptidase using immunocytochemical and molecular biological techniques. Successful execution of the proposed experiments will yield fundamental basic scientific insights into the molecular regulatory mechanisms associated with perireceptor events in chemosensory transduction and clinical insights into chemosensory transport disorders associated with anosmia and watery and mucoid rhinorrhea.

DESCRIPTION (from applicant's abstract): The goal of this training program is to prepare promising graduate and medical students, postdoctoral and medical resident fellows for successful careers in Cellular and Molecular Neuroscience of Sensory Systems. This program arises from the perceived benefits of integrated training in the fundamental principles which shape the function of all of our senses and is guided by the following conceptual framework: (I) The sensory systems of the human body are fundamental contributors to the health and well-being of people and are critical substrates for disease processes. (II) These neural systems share many core mechanisms of organization and function, which are especially apparent at the cellular, molecular and genetic levels. (III) Common mechanisms are also reflected in sensory pathologies- specific disease processes often impact multiple sensory systems. (IV) Graduate and postdoctoral research training which integrates cellular, molecular and genetic aspects over a range of sensory systems will enhance the ability of trainees to conduct innovative health-related research. Core mechanisms span multiple sensory systems as do disease processes (e.g. Charcot-Marie-Tooth disease, Norrie disease, Retinitis pigmentosa, Usher's syndrome, Aging and sensory senescence). Thus, there is a need for research training, which integrates across the traditional boundaries of each special-sense tissue. The proposed training faculty consists of 12 members with expertise in the auditory, chemosensory, mechanosensory and visual systems. Faculty research approaches range from mutagenesis and molecular genetics through cell and molecular biology, to intact animal physiology, behavioral analysis and clinical research. The institutional resources, level of extramural support and training histories of the training faculty engender a superb training environment.