The broad objective of this research proposal is to study interorgan glutamine metabolism in the tumor-bearing rat and investigate the causes and consequences of the glutamine depletion in advanced malignant disease. We hypothesize that the presence of advanced malignant disease alters interorgan glutamine metabolism, which is an integral part of nitrogen metabolism in critical illness and may be a significant component of cancer cachexia. Glutamine, the most abundant amino acid in blood and tissues, is the principal carrier of nitrogen from skeletal muscle to visceral organs. It is avidly consumed by gut-mucosal cells and tumor cells, which demonstrate a striking similarity between patterns of substrate utilization. With progressive malignant disease there may be excessive glutamine utilization by the tumor which contributes to a depletion of glutamine stores. A fall in circulating glutamine may alter intestinal glutamine metabolism and result in architectural changes in the gut mucosa. The research focuses on interorgan glutamine metabolism in the tumor-bearing rat. First, we will study the relationship between tumor size, food intake and circulating glutamine concentrations. Next, we will measure the flux of glutamine across the gut, liver, and hindquarter. By comparing glutamine exchange across the tumor- bearing and nontumor-bearing extremities, we will determine glutamine uptake by the growing tumor. We will then examine the consequences of glutamine depletion secondary to the tumor. We will study intestinal histology and cell proliferation and measure glutamine levels in muscle and liver. The activities of the glutamine synthetase and glutaminase enzymes will be measured. We will also study the regulation of plasma membrane glutamine transport in enterocytes and hepatocytes. Finally, the impact of glutamine feeding on interorgan glutamine metabolism in the tumor- bearing rat will be studied. This work is relevant to major health care problem since cancer is a principal cause of death and disability and is characterized by abnormal glutamine metabolism. Moreover, current parenteral amino acid solutions used to feed cancer patients do not contain glutamine. An improved understanding of glutamine metabolism in the host with advanced malignant disease not only provides further knowledge of alterations in intermediary metabolism and metabolic regulation in cancer, but also allows for the design of more specific and effective nutritional formulations which may require glutamine supplementation.
Showing the most recent 10 out of 68 publications
