This is a request for an ADAMHA Research Scientist Award (RSA). The brain is an information processor that generates behavior. The functional units for information transfer are the ionic channels in the neuronal membrane. This study aims to test the hypothesis that an etiological component underlying neuropsychiatric diseases such as affective disorders and schizophrenia may be a dysfunction of channel proteins. Our immediate goal is to understand how a channel protein works. To elucidate channel protein structure-function relationships a multidisciplinary yet focused approach encompassing techniques of membrane biophysics, molecular biology and protein engineering will be implemented. The strategy requires the primary structure of the protein to apply empirical secondary structure predictors in order to postulate a structural model. It is then followed by the design and synthesis of peptides proposed to be transmembrane functional components of the assembly (i.e. the """"""""pore"""""""" or the """"""""sensor"""""""") and the functional assay of the synthetic channel in lipid bilayers. A salient advantage is that, by chemical synthesis, an amino acid thought to be crucial for function can be substituted. The assay of the """"""""analogue"""""""" will establish is such residue is functionally significant. Concurrently, small perturbations in the structure of the protein will be produced by site directed mutagenesis of the gene followed by the functional assay of the mutant channel in membrane patches of Xenopus oocytes. The synthetic and the recombinant strategies complementing each other should provide an even more powerful path to establish structure-function relationships in channel proteins. This program will be initially focused on the voltage sensitive sodium channel and the nicotinic cholinergic receptor as prototypes of two major and distinct gene families in the brain. The ultimate goal is to blend psychiatry with the biology and chemistry of brain channel proteins as focused on structure-function correlations to gain new insights into the etiology of mental disorders. The direction of my professional growth has been and will continue to be guided by the goal of my research for the past 20 years: To reduce the complexity of the brain form and function to the language of chemistry.
Showing the most recent 10 out of 15 publications
