Transplantation of the upper gut will soon become a clinical reality and yet, while many studies have addressed the immunologic phenomena of the transplanted gut, little is known about the effects on the physiology of enteric function. Study of enteric physiology of the transplanted gut represents a new field with clinical and physiologic ramifications. This proposal has two relevant_and complimentary LONG TERM OBJECTIVES: to determine how intestinal transplantation alters gastrointestinal physiology and function; and to elucidate mechanisms of neural and hormonal control of motility and absorption via study or the denervated (transplanted) jejunoileum. Using a model of orthotopic autotransplantation of the entire jejunoileum to avoid con- founding effects of immune rejection/immunosuppression, Part A of this proposal expands a previous series of experiments on motility; Part B addresses neurohormonal control of absorptive physiology.
SPECIFIC AIMS. Part A--Motility: To determine how jejunoileal transplantation affects mechanisms controlling: 1) neural and hormonal control of motility patterns of the stomach and small intestine; 2) jejunoileal regulation of gastroduodenal motility and 3) gastroduodenal_regulation of jejunoileal motility. Part B- -Absorption: 1) To characterize temporal changes after jejunoileal transplantation in specific jejunal and ileal absorptive functions from the whole gut, and net absorption and transit or water, electrolytes, and nutrients in transplanted jejunal and ileal loops in vivo. 2) To focus on mechanisms in vivo studying elective denervations (vagal, sympathetic, both), and by study temporal changes after intestinal transplantation in: absorptive response to specific pharmacologic agents; tissue concentrations of regulatory endocrine and neurocrine peptides, cAMP, and brush border enzyme serosal electrodes and perfused intraluminal manometry catheters to measure motility in vivo by myoelectric and contractile activity. Absorption and transit will be assessed with radiolabelled foods and with intestinal perfusion and radiolabelled markers. Peptides will be evaluated using validated radioimmunoassays and immunohistochemistry. Morphologic analysis will use quantitative light microscopic morphometry and scanning electron microscopy. These experiments are directly relevant and will be clinically-applicable in understanding motor and absorptive aspects of the physiology of enteric function after intestinal transplantation.
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