The long term goal of this research is to understand the molecular mechanisms used by calcium to regulate and maintain cellular processes.
The specific aims for the renewal period are: 1) continue studies of the calmodulin system in normal and virus-transformed chicken embryo fibroblasts and 2) analyze the structure and function of synthetic calmodulins. Calmodulin is a highly conserved protein that is found in all eukaryotic cells examined and has multiple biochemical activities. Studies during the previous grant period have supported the theory that calmodulin is a pleiotropic regulator of cellular homeostasis. Multiple calmodulin binding proteins have been detected in subcellular fractions of CEF and several have been identified. The levels of some calmodulin binding proteins, like calmodulin levels, appear to be altered between normal and transformed cells. One calmodulin binding protein, myosin light chain kinase, is decreased in transformed cells. Emphasis during the renewal period will be on continued identification, characterization, quantitation and analysis of subcellular distribution of calmodulin binding proteins in normal and transformed fibroblasts. In order to gain insight into the molecular mechanisms utilized in calmodulin's interaction with binding proteins and drugs, a synthetic calmodulin gene was made to allow the production of a series of rationally designed calmodulins with systematic alterations in structure. These alterations are based upon known amino acid sequences of calmodulins with quantitative functional differences. In the short term, these studies will increase our knowledge of the molecular mechanisms utilized by calcium modulated proteins in stimulus-response coupling. In the longer term, these studies may provide the knowledge for the design of new calcium antagonists with increased biological specificity and might provide new insight into how quantitative perturbations of cellular homeostasis result in disease states.
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