Although the pancreas is a relatively small organ, tucked away in a corner of the digestive tract, its diseases have a disproportionately large impact on human health. These diseases include type I diabetes, pancreatitis and pancreatic cancer, and affect both the endocrine and exocrine compartments of the gland. The endocrine pancreas includes insulin-producing beta cells, resident in the islets of Langerhans, while the exocrine pancreas comprises digestive enzyme-secreting acinar cells andthe ducts through which their secretions are channeled to the gut. The research program of our lab reflects a conviction that a better understanding of pancreas developmental biology will promote efforts to treat or cure these diseases. In particular, we are interested in the intercellular signals that regulate pancreas development, as these may offer attractive targets for therapeutic intervention in pancreatic disease. We have shown that beta-catenin, an intracellular mediator of canonical Wnt signaling, is required in vivo for the initial formation of pancreatic acinar cells, and that canonical Wnt signaling components are expressed and apparently active in the embryonic and regenerating pancreas. The central hypothesis of the research proposed here is that development of acinar cells requires active Wnt signaling through the canonical, beta-catenin-dependent pathway. Furthermore, we hypothesize that this requirement applies not only to embryonic acinar development, but also to regeneration of acinar cells following injury. We propose three Specific Aims, using a combination of explant culture and mouse molecular genetics, to test these hypotheses. (1) We will establish the function of canonical Wnt signaling per se, including components upstream and downstream of beta-catenin, in the developing mouse pancreas. (2) We will determine the effects of beta-catenin deletion on the cell fate of pancreatic progenitor and precursor cells at multiple stages of organogenesis. (3) We will characterize the role of Wnt/beta-catenin signaling in the maintenance and injury-induced regeneration of adult acinar cells. Wnt signaling is critical to development and cancer in other organ systems, and our studies will delineate its potential roles in pancreatic organogenesis and regeneration. Furthermore, our research will generate critical insight into the mechanisms underlying adult pancreatic regeneration, a controversial phenomenon relevant to both stem cell therapeutics and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075072-04
Application #
7743777
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Serrano, Jose
Project Start
2007-02-15
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
4
Fiscal Year
2010
Total Cost
$297,342
Indirect Cost
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Kopinke, Daniel; Brailsford, Marisa; Pan, Fong Cheng et al. (2012) Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas. Dev Biol 362:57-64
Keefe, Matthew D; Wang, Hui; De La O, Jean-Paul et al. (2012) ?-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice. Dis Model Mech 5:503-14
Kopinke, Daniel; Brailsford, Marisa; Shea, Jill E et al. (2011) Lineage tracing reveals the dynamic contribution of Hes1+ cells to the developing and adult pancreas. Development 138:431-41
Barrott, Jared J; Cash, Gabriela M; Smith, Aaron P et al. (2011) Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome. Proc Natl Acad Sci U S A 108:12752-7
Murtaugh, L Charles (2008) The what, where, when and how of Wnt/beta-catenin signaling in pancreas development. Organogenesis 4:81-86