The Animal Core will provide the main animal model (conditional Kras[G12D] mouse model) to all four projects. Heterozygous LSL-Kras[G12D/+] mice will be crossed with heterozygous Pdx-1-Cre mice. Offspring will be genotyped for the presence of the mutated Kras allele and Cre transgene using PCR analysis of mouse tail DNA. Mutant mice {LSL-Kras[G12D/+];Pdx-1-Cre) will be randomly allocated to either the control diet (AIN-76A) or the high fat, high calorie diet (HFCD). Each of the experimental groups will then be allocated to the individual project-specific treatments and interventions. The Animal Core will conduct all aspects related to the Project-specific animal studies. Cohorts of mice will be sacrificed at 3, 6, 9, and 12 months or prematurely terminated according to the institutional guidelines. At sacrifice, tissues, including the entire pancreas, other organs and blood will be harvested and processed. The exact post-processing procedures depend on the individual Project requirements and needs. In general, half of the pancreas will be fixed in formalin and embedded in paraffin (for standard histology and immunohistochemistry), the other half frozen in liquid nitrogen (for RNA and protein analysis). A small piece of the pancreas will be used for genotyping (to detect the successful recombination event). Included in the Animal Core is the Pathology Sub-Core, which will provide the histo-pathological evaluation of all mouse tissues. Services that the Animal Core provides for each Project include: Obtaining and maintaining institutional approval, designing the animal studies in terms of logistics and statistical power calculations (together with Project Pi's and Biostatistics Sub-Core), maintaining animal strains and setting up breeding pairs, genotyping of all animals, randomization of animals to experimental groups, preparation and administration of experimental diets or interventions, daily monitoring and animal care, euthanasia of animals, harvest of tissues and blood at sacrifice, processing tissue, e.g. fixing in formalin and embedding in paraffin, and sectioning (together with the Pathology Sub-Core), histopathological evaluation of tissue sections (together with the Pathology Sub- Core), generation of cell cultures (PanlNs and murine pancreatic cancer), storage of raw data, central banking of tissues and biological samples, distribution of tissues to individual Projects, discussion of results with Project Leaders, training of Project investigators in animal procedures (if desired).

Public Health Relevance

The Animal Core's objectives are to minimize duplication of effort and reduce costs by coordinating the experiments performed by different Project Investigators so that animals and tissues may be shared by the investigators, where possible. Through the centralization, resources needed for the animal studies will be utilized very efficiently (as compared to the individual Projects performing their animal studies separately). Providing centralized animal services will ensure consistency in animal handling and data collection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA163200-03
Application #
8712202
Study Section
Special Emphasis Panel (ZCA1-RPRB-B)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$265,748
Indirect Cost
$72,345
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Liou, Geou-Yarh; Döppler, Heike; Necela, Brian et al. (2015) Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov 5:52-63
Young, Steven H; Rey, Osvaldo; Sinnett-Smith, James et al. (2014) Intracellular Ca2+ oscillations generated via the Ca2+-sensing receptor are mediated by negative feedback by PKC? at Thr888. Am J Physiol Cell Physiol 306:C298-306
Sinnett-Smith, James; Ni, Yang; Wang, Jia et al. (2014) Protein kinase D1 mediates class IIa histone deacetylase phosphorylation and nuclear extrusion in intestinal epithelial cells: role in mitogenic signaling. Am J Physiol Cell Physiol 306:C961-71
Lu, Qing-Yi; Zhang, Lifeng; Eibl, Guido et al. (2014) Overestimation of flavonoid aglycones as a result of the ex vivo deconjugation of glucuronides by the tissue *-glucuronidase. J Pharm Biomed Anal 88:364-9
Arensman, Michael D; Telesca, Donatello; Lay, Anna R et al. (2014) The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth. Mol Cancer Ther 13:2303-14
Kong, Ming; Zhu, Longdong; Bai, Li et al. (2014) Vitamin D deficiency promotes nonalcoholic steatohepatitis through impaired enterohepatic circulation in animal model. Am J Physiol Gastrointest Liver Physiol 307:G883-93
Rozengurt, Enrique; Soares, Heloisa P; Sinnet-Smith, James (2014) Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance. Mol Cancer Ther 13:2477-88
Ming, Ming; Sinnett-Smith, James; Wang, Jia et al. (2014) Dose-Dependent AMPK-Dependent and Independent Mechanisms of Berberine and Metformin Inhibition of mTORC1, ERK, DNA Synthesis and Proliferation in Pancreatic Cancer Cells. PLoS One 9:e114573
Edderkaoui, Mouad; Eibl, Guido (2014) Risk factors for pancreatic cancer: underlying mechanisms and potential targets. Front Physiol 5:490
Soares, Heloisa P; Ni, Yang; Kisfalvi, Krisztina et al. (2013) Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. PLoS One 8:e57289

Showing the most recent 10 out of 18 publications