EFRI-CBE: An Integrated Computational and Experimental Model for Biochemical and Electrical Interactions in Ion Channels and the Impact of Sialic Acid on Neuronal Function

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PI name: M.J. Betenbaugh Institution: Johns Hopkins University Proposal Number: 0736000 EFRI-CBE: An Integrated Computational and Experimental Model for Biochemical and Electrical Interactions in Ion Channels and the Impact of Sialic Acid on Neuronal Function AbstractThis interdisciplinary project brings together five complementary computational and experimental researchers to build an integrated and experimental analysis that can decipher how a change in the external environment in the form of a model insult (loss of sialic acid on a glycosylation site) is manifested in changes in the electrical properties of potassium channels that ultimately leads to paralytic behaviors in Drosophila organisms carrying this defect. Sialic acid was chosen to represent a model external biochemical stimulus, but the exact physiological role of this biochemical modification remains a relative poorly understood area especially in neuronal and in vivo animal models. To understand the effect of sialic aicd, the Principal Investigators (PIs) will utilize molecular scale dynamics simulations; create a Markov model of the kinetic and electrophysiological properties which connects to the molecular scale dynamics; and compare these predictions to experimental cell culture systems for different potassium Shaker family ion channels. This project will compare the neural behaviors predicted from molecular simulation, Markov models, and cell culture system to electrophysiology and behavior phenotypes of a Drosophila mutant in which the sialic acid gene is deleted. Understanding the role of the biochemical environment and particular sialic acid on electrical properties and cell dynamics will help one to identify possible methodologies for alleviating the symptoms, and potential pharmacological lipid agents to rescue or minimize the defect will be tested. This project will create a new interdisciplinary network of researchers with expertise in molecular modeling; ion channel modeling; electrophysiology, biochemical engineering, and Drosophila genetics to investigate the role that the biochemical environment, and in particular glycosylation and sialic acid, plays on electrical properties and function of ion channels, neuronal processes, and neurological disease. The group is drawn from a variety of different geographic institutions and diverse ethnic backgrounds, and two of the co-PI''s are female. The proposal will broaden the participation of high school and middle school students from underrepresented groups through an educational partnership with city school teachers in modeling the brain and brain disease. This program will excite students all the way from middle school and high school to graduate and post-doctoral levels about the integration of engineering and science by showing how behaviors and disease of the most complex organ, the brain, can be modeled and examined using experimental systems such as flies.