Cytokines on Olfactory Receptor Neuron Function

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DESCRIPTION (provided by applicant): The goal of this proposal is to provide a well-supervised, structured training program that will promote the development of the applicant's technical and intellectual skills necessary for success as an independent physician-scientist. This will be accomplished by a coordinated effort in the Johns Hopkins Department of Otolaryngology, the mentors' Basic Science Department of Molecular Biology and Genetics, and the Allergy and Asthma Center. The project will allow the candidate to pursue his interest in the mechanisms of olfactory loss in chronic sinusitis through a focused, mentored plan to study the effects of inflammatory mediators on olfactory receptor neuron (ORN) function. Research Program: Olfactory loss is a common symptom of chronic rhinosinusitis (CRS) that markedly diminishes quality of life of affected patients. The cellular and molecular mechanisms underlying olfactory dysfunction in CRS remain unknown. Recent studies by the PI show that some cytokines modulate calcium homeostasis in isolated ORNs. The central hypothesis of this proposal is that inflammatory mediators present in chronic rhinosinusitis directly modulate ORN function and promote the loss of olfaction through desensitization of the odor response. Accordingly, this proposal seeks to understand the effects of cytokines on ORN function in vitro and in vivo. Specifically, the applicant will 1) identify cytokine receptors on ORNs specific for mediators important in CRS and demonstrate the direct effects of these mediators on ORN odorant-induced responses; 2) develop a transgenic mouse model in which cytokines can be inducibly expressed in the olfactory epithelium; and 3) determine the effect of chronic exposure to cytokines on olfactory receptor neuron function and broadly assess the contribution of protein kinases, transcription factors, and cyclic nucleotides in this process. Training Program: The applicant will participate in a didactic program to enhance his career development. He will audit courses at Johns Hopkins University relating to ethics, research design, and the mechanisms of signal transduction. He will also participate in intellectual activities in Neuroscience, Otolaryngology, and Immunology. Frequent meetings with the sponsors will be arranged to monitor progress. Dr. Randall Reed, in whose laboratory the majority of the work will be performed, will provide primary sponsorship. Additional bench research will be performed in the laboratory of Dr. Schleimer, an established scientist with expertise in airway inflammation and cytokine modulation of cell function.