In principal the research objectives of this competitive renewal are similar to those on the original proposal in that the investigations are directed towards understanding the structural and functional correlates of the bile secretory apparatus. Considerable progress has been made with regard to our understanding of ligand transport from blood to the bile. In the present studies we will not limit our investigations to just those components which are present in bile, but will examine the molecular mechanisms which determine the ultimate fate of all the ligands under study. During the initial funding period of this grant, progress was made in the morphological identification of at least two intracellular transport pathways and the organelles involved were identified. The second funding period emphasized factors which perturbed the normal transport pathways such as, hormones, aging, drugs that effect the cytoskeleton and drugs which effect the endosome acidification. As a part of these studies a new intracellular pathway emerged namely, movement of epidermal growth factor (EGF) from the hepatocyte plasma membrane to the nucleus in pre-S phase regenerating liver. Equally surprising was the observation that following cholera toxin immunization large quantities of anti-cholera toxin specific IgG molecules entered into the bile by an apparently new secretory system. The previous studies took advantage of the state of the art methodology in light and the electron microscopic autoradiography, immunocytochemistry and column chromatography. Our present studies also use these vary basic investigative tools but also utilize cDNA probes, specific plasma membrane labeling, immunocytochemistry utilizing special embedding media and frozen sections for the electron microscope, SDS gels, western and northern blotting, fluorescent activated cell and organelle sorting and a variety of affinity columns for isolation of specific vesicles. The goal is to determine the molecular basis for ligand uptake, sorting, and processing and to understand the above phenomenon which perturb the normal system.
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