The overall objective of the studies proposed herein is the development of animal models that will then be used to examine the genetic basis of exocrine pancreatic cancer. Pancreatic cancer is the fourth most lethal cancer in the human population. It is typically diagnosed at an inoperable stage so that long term patient survival is exceptionally low. Increased understanding of the molecular pathogenesis of this disease may form a necessary foundation for attempts to reverse the poor prognosis. The development of transgenic animal technology has permitted the establishment of models of complex genetic diseases like cancer for which the effects of selected genetic alterations can be correlated with specific pathophysio-logical consequences in vivo. However, the transgenic approach has had several technical limitations, including lack of inducible systems for targeting transgene expression and the down regulation of transgene transcriptional regulatory elements in certain experimental contexts, such as neoplastic progression. The studies proposed in the application employ two recent advances in transgenic methodology, the tetracycline responsive system and the cre/lox recombinase system, to create models of exocrine pancreatic neoplasia that avoid the limitation described above and that should more closely reflect the etiological mechanisms believed to cause this disease in the human population. These models are then used to characterize the pathogenetic basis of the disease.
The specific aims are: (1) establish animal models of ductal neoplasia that reproduce the ductal origin of this cancer in humans; (2) characterize the pathogenic effects of genetic alterations that have been associated with the development and progression of exocrine pancreatic cancer in humans; and (3) determine, between species, the comparative pathogenicity of cancer- related genetic alterations.
The final aim generation of transgenic rat models of exocrine pancreatic cancer, addresses the fact that we must continually reason by analogy from one species to another when using animal models to study human disease. The goal of this aim is to directly compare, between species, the pathophysiological responses to identical, precisely defined genetic alterations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076361-05
Application #
6513323
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Mietz, Judy
Project Start
1998-09-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2002
Total Cost
$316,906
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Grippo, Paul J; Sandgren, Eric P (2012) Acinar-to-ductal metaplasia accompanies c-myc-induced exocrine pancreatic cancer progression in transgenic rodents. Int J Cancer 131:1243-8
Jorgenson, Tonia C; Williams, Bret R; Wendland, Allyson et al. (2010) Identification of susceptibility loci in a mouse model of KRASG12D-driven pancreatic cancer. Cancer Res 70:8398-406
Grippo, Paul J; Nowlin, Patrick S; Demeure, Michael J et al. (2003) Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res 63:2016-9
Grippo, P J; Sandgren, E P (2000) Highly invasive transitional cell carcinoma of the bladder in a simian virus 40 T-antigen transgenic mouse model. Am J Pathol 157:805-13