NEURAL SPECIFIC REGULATION OF PROOPIOMELANOCORTIN GENE E

Oregon Health And Science University, Portland OR

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Abstract

This Fogarty International Collaboration Award between the U.S. and Argentina is in support of the scientific goals outlined in its parent grant P01DK55819, "Neuroendocrine Control of Feeding and Metabolism" subproject 4, "Modulation of Feeding and Metabolism by Opioid Peptides." Obesity and its metabolic sequelae are major health problems world-wide. The opioid peptide beta-endorphin and a family of melanocortin peptides exhibit (POMC), that is expressed in specific populations of neurons within the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius in the brain stem. Both of these brain nuclei are key areas involved in the complex integration of neuroendocrine and autonomic control of a peptide and feeding. Recent genetic studies in human populations have strongly implicated the POMC gene as a quantitative trait locus for obesity and null mutations in molecular basis for neural-specific expression of the POMC gene, although we hypothesize that disordered POMC expression in the hypothalamus or brain stem may be a contributing factor to disorders of energy homeostasis. The goals of this project are to elucidate the transcriptional machinery responsible for POMC gene expression in the brain and to develop novel molecular tools for the further physiological characterization of POMC peptides and co-transmitters produced in POMC neurons in the control of appetite and feeding. These goals will be addressed by the following specific aims: 1) Identify a neural-specific enhancer(s) in the mouse POMC gene utilizing a deletional and mutational analysis in transgenic mice; 2) characterize putative transcriptional factors that interact with the neuronal in cancer; and 3) Develop an immortalized hypothalamic neuronal cell lines that expresses the POMC gene under regulation of known physiological mediators such as leptin.