The proposed research plan aims to characterize two neuronally expressed CIC chloride (CI-) channel isoforms in the model nematode Caenorhabditis elegans. Members of this ion channel family are important components in key cellular processes such as cell-membrane excitability, cell-volume regulation, transepithelial CI- transport, and acidification of intracellular organelles. CIC channels are present in organisms from bacteria to mammals, and the importance of these channels is underscored in humans, where mutations in four CIC genes cause distinct diseases. The research program will address fundamental questions concerning the physiological roles of different CIC isoforms in the nervous system, the assembly and composition of native channels, and the molecular mechanisms of channel function using a genetically tractable animal with complete genome sequence. An integrated approach incorporating genetic, molecular and electrophysiological methods is planned. ? Here the Candidate has an outstanding opportunity to apply her expertise in C. elegans genetics and to extend her interest in nervous system function through the application of electrophysiological techniques. The Sponsor's long-standing interest in the function of ion channels fuels his enthusiasm toward this effort to apply powerful genetic and molecular methods to this important, yet rather poorly understood, family of CI- channels. The laboratory is fully equipped for both C. elegans genetics and electrophysiology. The training program will include formal classes, lectures, and seminars as well as participation in national meetings focused on biophysics. In total, this program will ensure that the Candidate is skilled in both the theory and application of biophysical principles. This additional period of training will smooth the Candidate's transition back to academic research after several years in industry and allow her to develop a fully independent research program that will expand on the fundamental work proposed here ? ?
