The intestinal epithelium is the largest mucosal organ with a high capacity for self-renewal. Under normal conditions, cells of the intestine are quickly turned over and exhibit rapid cellular proliferation, especially within the crypt compartment where intestinal stem cells are located. Persistent inflammation in the intestinal tract may lead to the development of colitis, which is characterized by a loss of the intestinal epithelium integrity and infiltration of inflammatory lymphocytes. Findings from our laboratory have shown that Krüppel-like factor 5 [KLF5] is indispensable for proper maintenance of the crypt epithelium and that it plays an important role in the regeneration of intestinal epithelium by promoting epithelial repair after sustaining injuries. Our proposal focuses on developing novel small molecules that target KLF5. The long-term goal of this research proposal is to develop, characterize, and test novel therapeutic agents that enhance the regeneration of the intestinal epithelium.
Pancreatic cancer is the fourth most common cause of cancer-associated deaths in the U.S. More than 90% of pancreatic cancers are invasive malignant neoplasms with ductal differentiation, termed pancreatic ductal adenocarcinoma (PDAC). Pancreatic intraepithelial neoplasia (PanINs) comprise the most important type of precursors to PDAC. Activating mutations in KRAS are the earliest mutations found in this progression, and are present in over 90% of PDAC. Krüppel-like factor 5 (KLF5) is a transcription factor that regulates key cellular functions. Meta-analyses of data on differential expression of pancreatic tumor compared to normal tissue show overexpression of KLF5. Immunohistochemistry data show elevated expression of KLF5 in the cells comprising the dysplastic lesions in pancreatic cancer patient tumors. The hypothesis: KLF5 is critical for the formation of PanIN in Kras-induced tumorigenesis in vivo. The result of this study will be the basis for future investigations of KLF5 as a potential target for pancreatic cancer treatment.