METABOLISM AND FUNCTION OF CYCLIC NUCLEOTIDE

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A general, long standing interest of the applicant has been to understand the role(s) played by cyclic nucleotide phosphodiesterases (PDEs) in determining the amplitude and duration of second messenger cyclic nucleotide signals in the cell. It has always been clear that in order to do this one needs to know how many different PDEs are present in mammalian tissues, how and where they are expressed, and how they are regulated. Once identified and characterized it is then often possible to determine what functions are subserved by distinct PDE isozymes. This grant application outlines two phases of this process. First, we propose a continuation of our search for new PDEs and subsequent characterization of their kinetic and regulatory properties. One major difference compared to previous years is that we are now using more modern bioinformatic approaches for the initial aspects of this process. The second part of the application proposes specific examples for defining some the functions of one specific phosphodiesterase, PDE3B, as a modulator of growth factor and cytokine function in several different cell types. Specific examples include tests for the regulation by leptin stimulation of PDE3B of glucose metabolism in the liver, of cortisol synthesis in the adrenal and of feeding behavior in the hypothalamus. Similar approaches with other cytokines will also be carried out. These studies have the potential to define a whole new molecular mechanism of action for cytokines and a whole new general physiological role for PDE3B.