This is a resubmission of the renewal application for my Research Project Grant (R01) entitled """"""""Regulation of Differentiation in Esophageal Epithelia"""""""" (DK069984), which concluded on March 31, 2011. The overarching goal of this proposal is to understand the regulation of esophageal epithelial stratification, inflammation, and carcinogenesis through mechanistic studies of the key transcriptional regulator Kr|ppel-like factor 4 (KLF4). The significance of this proposal lies in (a) the prevalence of esophageal disorders, which are among the most common ailments in the United States and the world and (b) the important and emerging roles of KLF4 in the control of essential cellular processes in numerous tissues and cell types, including esophageal keratinocyctes. The PI is an experienced investigator who is an expert in the Kr|ppel-like factors (KLFs), animal models of disease, and esophageal squamous cell biology, and is supported by a superb research team, complemented by expert collaborators. In this proposal, we will take advantage of novel mouse models, which we have generated, and complementary in vitro systems utilizing two-dimensional and three-dimensional organotypic culture to test the hypothesis that KLF4 is a critical regulator within adult esophageal squamous epithelia, controlling processes such as keratinocyte migration and differentiation, the inflammatory response, and squamous cell cancer development. To explore the regulation of esophageal epithelial stratification, inflammation, and carcinogenesis by KLF4, we will undertake the following interrelated Specific Aims: (1) We will explore the function of KLF4 in esophageal epithelial migration and stratification (a) through mechanistic, epistatic studies of KLF4 and the KLF4 target WNT5A, a non-canonical Wnt, and (b) by identification of additional, relevant KLF4 target genes through functional genomics analyses~ (2) We will investigate the role of KLF4 loss in esophageal carcinogenesis by (a) examining the functional interaction of KLF4 and p53 in esophageal epithelial cells in vitro and in vivo, and (b) identifying the mechanisms of KLF4 loss in esophageal dysplasia and squamous cell cancer~ and (3) We will determine the mechanisms by which KLF4 promotes inflammation and the non-cell autonomous proliferative response by (a) evaluating the role of Rho Stases in NF:B activation by KLF4, (b) examining the effects of NF:B and TNF1 inhibition on proliferation of keratinocytes from ED-L2/KLF4 mice~ and (c) crossing ED-L2/KLF4 mice with esophageal-specific Ikk2 null mice. These complementary approaches will confirm and extend the findings from our current funding cycle, as outlined in Preliminary Data and our two recent publications in Gastroenterology. Moreover, the proposed research will be supported by the superb and collegial intellectual environment and the exceptional resources and facilities available to the PI and his team. We anticipate that these studies will provide insight into the factors that maintain normal esophageal epithelial homeostasis and the pathways that are disrupted in esophageal diseases, both benign and malignant.

Public Health Relevance

The studies proposed here will provide insight into the origins of esophageal diseases through studies of KLF4, a specific protein important for growth control and other vital cellular processes in the esophagus. We anticipate that the results obtained through this research will lead to new approaches to the diagnosis and treatment of esophageal disorders, which are among the most common and the most deadly ailments in the United States and throughout the world.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Carrington, Jill L
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Natsuizaka, Mitsuteru; Whelan, Kelly A; Kagawa, Shingo et al. (2017) Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat Commun 8:1758
Xu, Mingang; Horrell, Jeremy; Snitow, Melinda et al. (2017) WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation. Nat Commun 8:15397
Tetreault, Marie-Pier; Weinblatt, Daniel; Shaverdashvili, Khvaramze et al. (2016) KLF4 transcriptionally activates non-canonical WNT5A to control epithelial stratification. Sci Rep 6:26130
Maddipati, Ravikanth; Katz, Jonathan P (2016) KLF4 Initiates Acinar Cell Reprogramming and Is Essential for the Early Stages of Pancreatic Carcinogenesis. Cancer Cell 29:247-248
Tétreault, Marie-Pier; Weinblatt, Daniel; Ciolino, Jody Dyan et al. (2016) Esophageal Expression of Active I?B Kinase-? in Mice Up-Regulates Tumor Necrosis Factor and Granulocyte-Macrophage Colony-Stimulating Factor, Promoting Inflammation and Angiogenesis. Gastroenterology 150:1609-1619.e11
Yang, Yizeng; Katz, Jonathan P (2016) KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions. Cancer Biol Ther 17:422-9
Tetreault, Marie-Pier; Yang, Yizeng; Katz, Jonathan P (2013) Krüppel-like factors in cancer. Nat Rev Cancer 13:701-13
Stairs, Douglas B; Bayne, Lauren J; Rhoades, Ben et al. (2011) Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene. Cancer Cell 19:470-83
Tetreault, Marie-Pier; Yang, Yizeng; Travis, Jenna et al. (2010) Esophageal squamous cell dysplasia and delayed differentiation with deletion of krüppel-like factor 4 in murine esophagus. Gastroenterology 139:171-81.e9
Tetreault, Marie-Pier; Wang, Mei-Lun; Yang, Yizeng et al. (2010) Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice. Gastroenterology 139:2124-2134.e9

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