The pancreas shortly after each meal secretes the majority of the enzymes required for digestion of a diverse array of dietary components. To match the amount of available digestive enzymes to digestive need, both the synthesis of digestive enzymes and the size of the gland are regulated. This is in part via the hormones and neurotransmitters that stimulate digestive enzyme secretion, particularly cholecystokinin (CCK), but also by dietary components, particularly amino acids. It is the purpose of the proposed work to characterize this regulation, uncover the molecular mechanisms, and relate the stimulatory mechanisms to the integrative response.
Specific Aims of this proposal include: (1) determining the role and mechanism by which food, amino acids and CCK induce the synthesis of pancreatic digestive enzymes. We will first establish the time course and extent of enhanced pancreatic protein synthesis in mice after feeding. The state of activation of translation initiation factors, particularly elF2 and eIF4E, and p70 ribosomal S6 kinase will be evaluated. We will determine the effects of amino acids particularly leucine as a signal to initiate protein synthesis and activate the translation machinery. We will also determine the relative importance and synergy of CCK, amino acids and insulin in regulating protein synthesis. (2) We will determine the role by which CCK and amino acids enhance pancreatic growth. We will determine the effects of dietary protein in the absence of CCK on MAP kinase and other growth mediating pathways, and we will determine if diet-induced growth in the absence of CCK is dependent on calcineurin, similar to the effect of CCK with a normal diet. (3) We will determine the mechanism of calcineurin in induction of pancreatic protein synthesis and growth. Whether activated calcineurin is sufficient to induce growth and protein synthesis will be determined. We will also determine whether calcincunn-induced gene regulation is involved in the growth response. These studies will be carried out in normal mice fed different diets or gavage-fed trypsin inhibitor or amino acids. They will also make use of a mutant mouse line with CCK-deleted and involve the construction of a transgenic mouse line with constitutively active calcineurin targeted to the pancreas. Studies will be carried out both in vivo and in isolated pancreatic acini. Immunosuppressants such as cyclosponn A and FK506 will be used to inhibit calcineurin and rapamycin to inhibit mTOR. This work, in addition to understanding normal function may assist in designing diets to maximally stimulate pancreatic growth to counteract pancreatic insufficiency.
| Holtz, Bryan J; Lodewyk, Kevin B; Sebolt-Leopold, Judith S et al. (2014) ERK activation is required for CCK-mediated pancreatic adaptive growth in mice. Am J Physiol Gastrointest Liver Physiol 307:G700-10 |
| Guo, Lili; Sans, Maria Dolors; Hou, Yanan et al. (2012) c-Jun/AP-1 is required for CCK-induced pancreatic acinar cell dedifferentiation and DNA synthesis in vitro. Am J Physiol Gastrointest Liver Physiol 302:G1381-96 |
| Gurda, Grzegorz T; Wang, Jackie Y; Guo, LiLi et al. (2012) Profiling CCK-mediated pancreatic growth: the dynamic genetic program and the role of STATs as potential regulators. Physiol Genomics 44:14-24 |
| Sans, Maria Dolors; Sabbatini, Maria Eugenia; Ernst, Stephen A et al. (2011) Secretin is not necessary for exocrine pancreatic development and growth in mice. Am J Physiol Gastrointest Liver Physiol 301:G791-8 |
| 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 |
| Gurda, Grzegorz T; Crozier, Stephen J; Ji, Baoan et al. (2010) Regulator of calcineurin 1 controls growth plasticity of adult pancreas. Gastroenterology 139:609-19, 619.e1-6 |
| Williams, John A (2010) Regulation of acinar cell function in the pancreas. Curr Opin Gastroenterol 26:478-83 |
| Lee, SaeHong; Wishart, Matthew J; Williams, John A (2009) Identification of calcineurin regulated phosphorylation sites on CRHSP-24. Biochem Biophys Res Commun 385:413-7 |
| 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 |
| Crozier, Stephen J; Sans, Maria Dolors; Lang, Charles H et al. (2008) CCK-induced pancreatic growth is not limited by mitogenic capacity in mice. Am J Physiol Gastrointest Liver Physiol 294:G1148-57 |
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