The size and secretory capacity of the pancreas are diminished during protein malnutrition (PMal); however, these aberrations are rapidly reversed following ingestion of dietary protein. The goal of this work is to elucidate the molecular mechanisms whereby the loss of dietary protein results in pancreatic dysfunction and its return facilitates recovery. It is proposed that the effects of dietary protein on pancreatic recovery are mediated primarily by amino acids and CCK. Therefore, the individual contribution of amino acids and CCK on both growth and secretion will be determined. These studies will elucidate whether activation of two signaling pathways implicated in other models of pancreatic growth, calcineurin and mTOR, is necessary for improved pancreatic growth and secretory capacity following PMal. Individual proteins whose expression is altered during recovery from PMal will be identified in vivo and a cultured acinar cell model will be developed to assess the contribution of selected candidate proteins to the recovery from PMal. PMal will be induced in mice through feeding of a protein deficient diet. Studies on pancreatic growth will be carried out in normal and CCK-deficient mice fed various diets, as well as in differentiated murine acinar cells under varying culture conditions. Changes in cell size and structure will be studied using quantitative morphometry. Secretion will be measured in vitro as well as in vivo via cannulation of the pancreatic duct. The effects of signaling pathway activation will be assessed using pharmacological inhibitors. Alterations in protein expression will be assessed in vivo by polysome profiling and gene chip array. The contribution of these proteins to pancreatic recovery will be elucidated in vitro using shRNA and adenoviral vectors. This work will provide important insight into the regulation of macronutrient digestion and the role of dietary protein in pancreatic function. Digestion of food and delivery of nutrients throughout the body is dependent upon the enzymes produced in the exocrine pancreas. Individuals lacking protein in their diet often have pancreatic dysfunction and are unable to properly digest food. It is the purpose of this research is to understand how dietary protein maintains pancreatic health. ? ? ?
| Crozier, Stephen J; Sans, M Dolors; Wang, Jackie Y et al. (2010) CCK-independent mTORC1 activation during dietary protein-induced exocrine pancreas growth. Am J Physiol Gastrointest Liver Physiol 299:G1154-63 |
| Crozier, Stephen J; D'Alecy, Louis G; Ernst, Stephen A et al. (2009) Molecular mechanisms of pancreatic dysfunction induced by protein malnutrition. Gastroenterology 137:1093-101, 1101.e1-3 |
