POLYAMINES IN THE REGULATION OF GASTROINTESTINAL GROWTH

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The overall objective of this proposal is to study and define the role of the polyamines putrescine, spermidine, spermine and cadaverine in the role of the polyamines putrescine, spermidine, spermine and cadaverine in the regulation of gastrointestinal growth. Growth of the gut will be studied under in vivo and in vitro conditions after various experimental interventions which induce gastrointestinal growth. The role of the polyamines will be studied under the outline provided by the following specific aims: 1. To study and define the role of intraluminal polyamines for prokaryotic and eukaryotic sources as regulators of mucosal growth. 2. To study the polarization of gastrointestinal epithelial cell and the vectorial movement of polyamines in these cells. 3. To study the trophic effects of various growth factors and their relationship to polyamine-dependent growth in the gastrointestinal tract. The importance of understanding the regulation of this process is underscored by the realization that many diseases of the gastrointestinal tract are, in fact, disorders of mucosal growth. Esophageal reflux, chronic gastritis, Zollinger-Ellison hyperproliferative mucosa. The polyamines are a group of ubiquitously distributed polycations which are required for normal growth and differentiation; the goal of this work is to elucidate the role of the polyamines during mucosal growth. It is proposed to study the availability of polyamines derived from colonic microfloral polyamine metabolism in gnotobiotic and axenic rats. Experiments have been designed to study the direct effects of putrescine to stimulate DNA synthesis in a duodenal crypt cell line (IEC-6) in culture. The IEC-6 cell line will also be used to study polyamine uptake from both apical and basolateral sides of this cell. The movement of polyamines into the GI epithelial cell will be confirmed in the whole animal. Finally, it is proposed to relate the growth promoting effects of various trophic factors to their ability to modulate polyamine metabolism. These experiments will be used to determine whether polyamines serve as a common mediator during stimulation of mucosal growth or if they serve only a permissive role.