Using rat exocrine pancreas, we have recently demonstrated that alkalinization of the acinar lumen by ductal bicarbonate secretion regulates endocytosis at the apical plasma membrane of the acinar cell. this pH dependent endocytic process, representing coupling of duct cell and acinar cell function, is associated with (I) the release of GP 2, a glycosyl phosphatidylinositol (GPI) anchored protein, from the apical plasma membrane; and (ii) the activation of tyrosine kinases, specifically src. In addition, alkalinization of the acinar lumen is required for solubilization of proteins secreted from the acinar cell. Conversely, lack of alkalinization of the acinar lumen leads to a dramatic increase in the apical membrane surface area of acinar cells due to inhibition of endocytosis as well as the formation of precipitates with the acinar lumen as assessed by electron microscopy. We have found similar morphologic changes in mice homozygous for the Cystic Fibrosis gene deletion (CFTR -I-), a condition which bicarbonate secretion into the acinar duct lumen is inhibited. We hypothesize that alkalinization of the acinar lumen via ductal bcaronate secretion mediates pH dependent cleavage of glycolipid anchored proteins such as GP 2 to activate endocytosis at the apical plasma membrane. This proposal will build upon these observations and eterine (I) whether pH dependent cleavage of GPI anchored proteins plays a role in activation of apical membrane endocytosis; (ii) whether impaired alkalinization of the acinar lumen in vivo in C mice leads to selective inhibition of apical endocytosis, and (iii) the signal transduction pathway through which apical endocytosis is regulated. Results from this project will determine the mechanism by which lumenal pH regulates endocytosis at the apical surface of the acinar cell as well as define the mechanism by which pancreatic dysfunction may occur in Cystic Fibrosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine A Subcommittee 2 (GMA)
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Beth Israel Deaconess Medical Center
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Zaman, Munir M; Martin, Camilia R; Andersson, Charlotte et al. (2010) Linoleic acid supplementation results in increased arachidonic acid and eicosanoid production in CF airway cells and in cftr-/- transgenic mice. Am J Physiol Lung Cell Mol Physiol 299:L599-606
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Blanco, Paola G; Zaman, Munir M; Junaidi, Omer et al. (2004) Induction of colitis in cftr-/- mice results in bile duct injury. Am J Physiol Gastrointest Liver Physiol 287:G491-6
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