This proposal describes a five year integrated mentored training program for the development of an academic basic science research career in pancreatology. The Principal Investigator has completed a clinical fellowship in Gastroenterology and seeks to build on his existing research experience and skills to become a successful independent investigator in an area of research that requires additional multi-disciplinary training. The Investigator will acquire a unique skill set to study stromal-epithelial interactions in pancreatic disease. While recognized to be important to our understanding of adult pancreatic diseases, such as pancreatitis and preneoplasia, little is known regarding crosstalk between the stroma and epithelium. To dissect this phenomenon, the Investigator will integrate concepts from pancreas development and stem cell biology through formal coursework, mastering of relevent [sic] techincal [sic] skills, and mentorship by experts in these fields. The Investigator has identified two renowned physician-scientists to aid in the acquisition of this expertise and in his professional development. Dr. Ben Stanger, a well-trained physician-scientist, is an authority in pancreas development and the study of developmental signaling pathways using genetic mouse models. Dr. Anil Rustgi, Chief of Gastroenterology at the University of Pennsylvania, is renowned for his work in the application of developmental principles to the understanding of gastrointestinal diseases, including cancer. Additionally, an advisory committee comprised of respected NIH-funded investigators has been formed to provide scientific and professional guidance. With the mentorship of these qualified individuals, a research program dissecting stromal-epithelial interactions in the adult pancreas will be established. For the past two years, the Investigator has developed techinques [sic] to study primary pancreatic myofibroblasts and epithelial cells from novel mouse models of pancreatic disease. Using these methods, myofibroblasts, a major component of the pancreatic stroma, were shown to facilitate the dedifferentiation and proliferation of pancreas epithelial cells in co-culture. Conversely, epithelial cells produced phenotypic [sic] changes in co-cultured myofibroblasts. Pharmacologic inhibition of the Notch and Hedgehog pathways augmented these effects. Since these inhibitors are known to affect other pathways, the proposed experiments will determine the nature and contribution of Notch and Hedgehog signaling in mediating stromal-epithelial interactions using novel genetic approaches in vitro and in vivo. The combined resources available to the Investigator at the University of Pennsylvania, including the NIDDK-funded Center for Molecular Studies in Digestive and Liver Diseases, will provide an environment conducive to the completion of the training component of this grant, execution of the proposed research program, and development of a unique line of investigation in pancreatology that will serve as a springboard for the Investigator's career as an independent physician-scientist.

Public Health Relevance

Pancreatitis and PanIN, the precursor to pancreatic cancer, are two of the most prevalent and deadly diseases of the pancreas for which no good treatments are available. Our studies will examine how epithelial and stromal cells, the two different cell types in the pancreas involved in these diseases, interact. Through understanding how these cells cooperate, we hope to shed new light on the development of new ways of diagnosing and treating these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK088945-04
Application #
8496024
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$152,971
Indirect Cost
$11,331
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Rhim, Andrew D; Thege, Fredrik I; Santana, Steven M et al. (2014) Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. Gastroenterology 146:647-51
Rhim, Andrew D; Oberstein, Paul E; Thomas, Dafydd H et al. (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735-47
Sreekumar, Bharath K; Belinsky, Glenn S; Einwachter, Henrik et al. (2014) Polarization of the vacuolar adenosine triphosphatase delineates a transition to high-grade pancreatic intraepithelial neoplasm lesions. Pancreas 43:1256-63
Helgadottir, Holmfridur; Metz, David C; Yang, Yu-Xiao et al. (2014) The effects of long-term therapy with proton pump inhibitors on meal stimulated gastrin. Dig Liver Dis 46:125-30
Shah, Pari; Rhim, Andrew D; Haynes, Kevin et al. (2014) Diagnosis of pernicious anemia and the risk of pancreatic cancer. Pancreas 43:422-6
Rhim, Andrew D (2013) Epithelial to mesenchymal transition and the generation of stem-like cells in pancreatic cancer. Pancreatology 13:114-7
Hamilton, Kathryn E; Noubissi, Felicite K; Katti, Prateek S et al. (2013) IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts. Carcinogenesis 34:2647-54

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