Nicholas O. Davidson, MD, DSc
John E. and Adaline Simon Professor of Medicine and of Developmental Biology
Chief, Division of Gastroenterology
Director, Digestive Disease Research Core Center
“Our laboratory is interested in complex lipid trafficking from cells of the small intestine and liver. We are interested several abundantly expressed genes including apolipoproteinB (apoB) and microsomal triglyceride transfer protein (Mttp), both of which are indispensable for lipid export from enterocytes and hepatocytes. We are also interested in the role of a major cytoplasmic lipid binding protein, L-Fabp, which regulates fatty acid trafficking in the liver and small intestine. We have generated mouse lines in which deletions or mutations of these genes have been engineered to reproduce important models of human lipid storage defects as well as models of conditional lipotoxicity. These models permit detailed analysis of the pathways leading to hepatic steatosis and the impact on systemic lipoprotein metabolism. We are interested in the possibility that polymorphisms in the corresponding human genes may be informative in determining susceptibility and progression of NAFLD. Our other area of interest is post-transcriptional regulation of gene expression in mammalian intestine, particularly the role of RNA binding proteins in modulating inflammation and carcinogenesis. Our laboratory cloned a prototype RNA-binding protein, apobec-1, that modifies apoB RNA in a tissue-specific manner. We have investigated the function of apobec-1 using gain and loss of function approaches in cell culture and in gene targeted mice. An important advance was the demonstration that apobec-1 binds to RNA using a high affinity consensus element, which is present in the 3′ untranslated regions (3’ UTRs) of several A+U-rich RNAs including numerous cytokine transcripts and also the 3’ UTR of cyclooxygenase 2 (cox-2). Binding of apobec-1 to cox-2 mRNA altered mRNA stability and changed protein expression in both cell lines and genetically manipulated mice. Alterations in cox-2 gene expression are an important and predictable feature of intestinal tumor development, and we are interested in the role of apobec-1 expression in genetic models of colorectal cancer, particularly murine models of the human disease Familial Adenomatous Polyposis. Mice with genetic deletion of apobec-1 are protected against intestinal adenoma formation, suggesting that apobec-1 may be a relevant genetic modifier of polyposis and potentially colorectal cancer. We are interested in the possibility that alterations in the expression of apobec-1 may be relevant to the changes in cox-2 gene expression accompanying certain GI cancers in humans. We are also interested in another RNA binding protein, apobec-1 complementation factor (ACF). ACF is structurally related to the HuR family of A+U-rich RNA binding proteins, members of which have been shown to play a role in colon carcinogenesis. We have generated lines of gene targeted mice with ACF deletion and will be examining the role of ACF in murine intestinal adenoma formation.”
Dr. Davidson was appointed chief of the Division of Gastroenterology in October 1998. After medical school and residency training at Kings College Hospital Medical School, London, Dr. Davidson entered the clinical scholar program at Rockefeller University, New York. He then moved to Columbia-Presbyterian Medical Center, New York, where he completed his gastroenterology fellowship training. In 1986, Dr. Davidson joined the faculty of the University of Chicago, where he remained until 1998, eventually leaving to become the division chief at Washington University as Professor of Medicine and of Molecular Biology and Pharmacology (since 2008, known as the Department of Developmental Biology). Dr. Davidson’s major research interests are in the molecular genetics of lipid transport and in the post-transcriptional regulation of gene expression, particularly RNA editing and mRNA stability. His clinical interests are in the molecular genetics of hereditary colorectal cancer syndromes, particularly Familial Adenomatous Polyposis.