OPIATE PEPTIDES AND RECEPTORS IN THE FAT/FAT MICE

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The candidate, Dr. Yemiliya Berman, holds a Ph.D. degree from the Institute of Molecular Biology, Moscow, Russia. She is a Research Assistant Professor in the Department of Pharmacology at the New York University Medical Center. The long-term career goals will be to gain an understanding of opioid peptides and their involvement in modulating physiological functions. New York University Medical Center and R. L. Devi's laboratory provides the intellectual environment necessary for the development of a strong research program. In addition, Dr. L. Devi will advise and guide the candidate to become an independent scientist, committed to a productive biomedical research career. The candidate's career goal is to investigate the role of the opioid system in a mouse model for obesity fat/fat. This mouse model is deficient in carboxypeptidase E, an enzyme involved in the maturation of opioid peptides and a regulated secretory pathway sorting receptor. In the brain of fat/fat mice there is a large decrease in fully processed opioid peptides and a large increase in the level of COOH- terminal extended peptides, high molecular weight dynorphin containing peptides and unprocessed prodynorphin. In this grant application the regional distribution of ir-dynorphin and ir-enkephalin peptides and mRNA levels in adult and developing brains of fat/fat mice will be examined (specific aim 1). These studies will provide information on the differential distribution and developmental variations in the levels of opioid peptides. The effect of changes in the levels of dynorphin peptides on the opiate receptor system will be examined in adult and developing fat/fat mice (specific aim 2). Total receptor number and agonist stimulated GTP [g-35S] binding will be measured by autoradiography and adenylyl cyclase activity will be used for functional quantification of microns, delta and kappa opioid receptors. These studies will help to understand how the opiate receptor system adapt to incomplete peptide processing. The hypothesis that impaired Prodynorphin processing in the fat/fat mice is a result of incorrect sorting and secretion in an unregulated manner will be evaluated (specific aim 3). These studies will provide information on how CPE obliteration leads to incomplete Prodynorphin processing and release abnormalities. The responsiveness of fat/fat and lean littermate mice to microns, delta and kappa agonists and antagonists in terms of their feeding behavior will be examined (specific aim 4). Agonists or antagonists will be administered acutely and cumulative food intake in the one hour following injection will be determined. Dose response curves will be generated. These studies will provide information on opioid receptor types involved in feeding of fat/fat mice and development of obesity.