Molecular and Cellular Mechanisms Regulating Exocrine Pancreas Growth and Regeneration

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Keefe, Matthew David
Title Molecular and Cellular Mechanisms Regulating Exocrine Pancreas Growth and Regeneration
Date 2014-08
Description The pancreas is a complex organ consisting of both an endocrine and exocrine function. Cells of the endocrine pancreas control blood sugar, while the exocrine pancreas is responsible for providing enzymes used in digestion of food. These enzymes are synthesized by acinar cells, which comprise the majority of the organ. The work in this dissertation demonstrates that after birth, acinar cell proliferation, nuclearity, and ploidy are controlled by the signaling protein β- catenin as well as by novel intrinsic and extrinsic signaling factors, essential for postnatal and adaptive growth. This work establishes that β-catenin is acting not as a mitogen itself, but as a rheostat to tune the proliferative input from other sources. To test our rheostat model, we demonstrate that cholecystokinin (CCK)- dependent growth, an adaptive response to increased metabolic demand, requires β-catenin signaling to maximize acinar cell proliferation. We have also determined that mononucleate acinar cells preferentially contribute to early postnatal and regenerative growth, indicating the existence of subpopulations within the exocrine pancreas with distinct capacities for growth. Though binucleate acinar cells are initially inhibited from dividing, they regain the ability to divide in the adult organ. Though overall acinar cell proliferation in the adult organ is rare, the division of binucleate acinar cells produces a significant fraction of tetraploid, mononucleate acinar cells in the adult pancreas. When acinar cells iv# # undergo regenerative proliferation in response to injury, however, cell cycle entry becomes restricted to mononucleate cells, recapitulating early postnatal expansion and protecting against the generation of aneuploid-vulnerable offspring. Taken together, this work demonstrates how the normal mass of acinar cells is attained and sustained in the mouse pancreas, as a genetic model for control of vertebrate organ size and a foundation for understanding diseases of the exocrine pancreas such as pancreatitis and pancreatic cancer.
Type Text
Publisher University of Utah
Subject MESH Pancreas; Pancreas, Exocrine; Organogenesis; Acinar Cells; beta Catenin; Regeneration; Pluripotent Stem Cells; Pancreas; Cell Proliferation
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of Molecular and Cellular Mechanisms Regulating Exocrine Pancreas Growth and Regeneration
Rights Management Copyright © Matthew David Keefe 2014
Format Medium application/pdf
Format Extent 28,036,013 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6vj0212
Setname ir_etd
Date Created 2019-03-11
Date Modified 2021-05-06
ID 1404032
Reference URL https://collections.lib.utah.edu/ark:/87278/s6vj0212
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