The pancreas is an organ that has endocrine (islet lineage) and exocrine compartments (acinar and ductal lineage). The ductal tree consists of terminal, or intercalated, ducts that interface with acini or centroacinar cells, which are potentil sites of progenitor cells. Intercalated ducts merge to form intralobular ducts, and these in turn merge to form interlobular ducts, and finally, into the main duct that traverses the pancreas to the duodenum, delivering fluid laden with digestive enzymes. We have emphasized studies (in the previous cycle) on the governance of the regulation of ductal branching morphogenesis. Using this as a platform, we now wish to elucidate the transcriptional programs that regulat ductal development, but in particular regulate the emergence of ductal structures during acinar-ductal metaplasia (ADM) and the transition of normal ducts to preneoplastic ducts (termed PanIN). We hypothesize that a newly discovered homeodomain transcription factor, Prrx-1, is critical in ductal cell morphogenesis, acinar-ductal metaplasia, and re-neoplasia. This hypothesis will be pursued by the following Specific Aims through complementary in vitro and rigorous in vivo approaches: (1) To elucidate the mechanistic underpinnings of Prrx1 in ADM and PanIN. We will determine the functional roles of Prrx1+ cells in ADM through genetic lineage tracing studies in vivo. We will define the dependence of pancreatic regeneration after ADM through the pancreatic conditional knockout of Prrx1. We will determine if Prrx1+ cells are more susceptible to the effects of oncogenic KrasG12D in the development of PanIN. (2) To determine the gene targets of Prrx1 through CHiP-Seq, to validate specific gene targets identified in preliminary analysis and determine their functiona relationships. (3) To delineate the functional differences between Prrx1 isoforms in the roles in ADM and PanIN: the role of Prrx1b in self-renewal of cells and role of Prrx1a in invasion. Our novel insights and innovative approaches will for the first time help to mechanistically characterize a transcriptional factor that is critical in ductal development, ADM and PanIN, and place this gene as potentially as important as Pdx1 in the endocrine lineage and Ptf1a (p48) in the acinar lineage. These studies will help to provide opportunities for management of pancreatitis to enhance tissue regeneration and of PanIN/PDAC.

Public Health Relevance

Pancreatic diseases represent a great public health burden. Elucidation of the mechanisms underlying pancreatic development, regeneration and preneoplasia will help improve diagnosis and therapy in patients afflicted with these diseases.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Rustgi, Anil K (2014) Familial pancreatic cancer: genetic advances. Genes Dev 28:1-7
Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong et al. (2014) SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas. J Clin Invest 124:1636-45
Bhattacharya, Sabyasachi; Katlinski, Kanstantsin V; Reichert, Maximilian et al. (2014) Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury. EMBO Mol Med 6:384-97
Rustgi, Anil K (2013) A historical perspective on clinical advances in pancreatic diseases. Gastroenterology 144:1249-51
Reichert, Maximilian; Takano, Shigetsugu; Heeg, Steffen et al. (2013) Isolation, culture and genetic manipulation of mouse pancreatic ductal cells. Nat Protoc 8:1354-65
Botta, Gregory P; Reichert, Maximilian; Reginato, Mauricio J et al. (2013) ERK2-regulated TIMP1 induces hyperproliferation of K-Ras(G12D)-transformed pancreatic ductal cells. Neoplasia 15:359-72
Reichert, Maximilian; Takano, Shigetsugu; von Burstin, Johannes et al. (2013) The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. Genes Dev 27:288-300
Botta, Gregory P; Reginato, Mauricio J; Reichert, Maximilian et al. (2012) Constitutive K-RasG12D activation of ERK2 specifically regulates 3D invasion of human pancreatic cancer cells via MMP-1. Mol Cancer Res 10:183-96
Reichert, Maximilian; Rustgi, Anil K (2011) Pancreatic ductal cells in development, regeneration, and neoplasia. J Clin Invest 121:4572-8
Pinho, Andreia V; Rooman, Ilse; Reichert, Maximilian et al. (2011) Adult pancreatic acinar cells dedifferentiate to an embryonic progenitor phenotype with concomitant activation of a senescence programme that is present in chronic pancreatitis. Gut 60:958-66

Showing the most recent 10 out of 22 publications