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gmueller@usuhs.mil
Ph.D., Michigan State University, 1976
Our research investigates the cellular and molecular mechanisms controlling peptide secretion from neurons and endocrine cells. Neuroendocrine peptides are essential to an organism's physiology and response to environmental and pharmacologic challenges. Their structures, and thus their roles in intercellular communication, are determined by the genes that encode them and by the actions of processing enzymes which liberate the peptides from their protein precursors. Recent cloning of several processing enzymes makes possible the direct study of how gene expression and processing enzymes interact to regulate peptidergic transmission. Our research focuses on the peptide alpha-amidating enzyme, peptidylglycine alpha-amidating monooxygenase (PAM), as a prototype processing enzyme. Alpha-amidation is a rate limiting step in peptide biosynthesis and is required for the activity of more than half of the peptides utilized in intercellular communication. We study the regulation of PAM and how it is coordinated with the production and release of alpha-amidated peptides by the pituitary gland and brain neurons. In addition to investigating the physiologic mechanisms that coordinate the expression and activity of PAM with those of its substrates and products, we are determining the possibility that PAM may be a therapeutic target for nutritional interventions and drug actions. Most recently, we have initiated an investigation of the role of PAM in mediating the amidation of fatty acids. Fatty-acid amides are a new class of intercellular messenger. The class consists of two families, the primary fatty-acid amides as represented by the sleep-inducing compound oleamide, and the ethanol-amides as represented by anandamide (arachidonoyl ethanolamide), the endogenous ligand of the cannabinoid receptor. Based upon these two examples it is likely that fatty-acid amides have a broad range of functions in physiologic regulation.
In 2007 we reported the remarkable discovery that cytochrome c functions as an enzyme to catalyze the synthesis of oleamide. Cytochrome c is intriguing for its central rolls in both cell viability and death. Its role in mitochondrial electron transport and energy production supports life, whereas, its release from mitochondria initiates the apoptotic pathway for programmed cell death. We have observed that during apoptosis oleamide production is dramatically up-regulated, presumably due to the actions of cytochrome c. At present, therefore, there appear to be two mechanisms for the biosynthesis of bioactive lipid amides, one via PAM and the other via cytochrome c. We presume these two mechanisms mediate different biologic functions. Overall, our research involves biochemical, molecular, in vitro, physiologic and behavioral techniques and is conducted in collaboration with labs at USU and Johns Hopkins University.
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