The development and function of the ACTH/-endorphin system of peptides will be examined in the arcuate region of the hypothalamus, the anterior pituitary, and the intermediate pituitary. This system of peptides is implicated in a wide variety of normal nervous functions (e.g. analgesic) and may be importantly involved in several disorders. Developmental questions to be examined will center on when the tissue-specific post-translational processing steps are first detectable, and on what cellular and molecular forces or influences are acting to produce differences in post-translational processing. It is expected that periods of plasticity will be detected--times when abnormal developmental cues, drugs, etc. will re-direct development of a tissue into an abnormal pattern. Monoclonal antibody technology will be used to examine the similarities and differences in the cell surface proteins of ACTH/endorphin cells in the hypothalamus, anterior pituitary, and intermediate pituitary; monoclonal antibodies will then be used to probe the function of those common and unique cell surface proteins. Several of the cellular aspects of hypothalamic and pituitary ACTH/endorphin secretion will be investigated in culture and in vivo. The cellular events just prior to secretion (packaging in secretory granules, terminal steps in post-translational processing) and the molecular nature of the various peptides released will be studied; special attention will be given to the """"""""minor"""""""" modifications of the peptides (such as amidation, acetylation, and COOH-terminal proteolysis) which can have dramatic effects on the biological potency of the peptides. Possible regulation of secretion by previously secreted peptides will be more thoroughly probed, and possible changes in intracellular post-translational processing will be examined in various states of secretion. The post-translational processing and secretion of pro-ACTH/endorphin-derived peptides will also be probed in the lizard, an animal with a firmly established role for a melanocyte stimulating peptide. A dominant theme will be to understand how different tissues can utilize the same or a very similar common precursor molecule to produce and secrete differing blends of biologically potent peptides.
