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Nicholas O. Davidson, M.D. |
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Washington University Dept. of Medicine tel: (314) 362-2027 |
RESEARCH INTEREST We study two areas. The first is gene regulation through alterations in mRNA stability and posttranscriptional editing. Our laboratory cloned the catalytic subunit of the apoB RNA editing enzyme, an RNA-specific cytidine deaminase, apobec-1. We have mapped a high affinity binding site for apobec-1, which, interestingly, is present in a number of AU-rich RNA targets including c-myc, COX-2, TNF-α and IL-2 mRNAs. Moreover, apobec-1 binding alters mRNA stability of these targets in both cell lines and animal tissues. Apobec-1-/- mice demonstrate reduced COX-2 mRNA stability in vivo. COX-2 regulates production of intestinal prostaglandins, one of which, PGE2, is a survival factor for enterocytes following radiation injury and is an important predictor of colonic polyp development. Genetic intercrosses of apobec-1-/- mice with a strain of mice susceptible to colorectal cancer show decreased levels of COX-2 and reduced tumor burden. We have recently identified a cluster of apobec-1-related genes as well as a family of RNA binding proteins that function as apobec-1 partners. Both of these areas represent future targets for investigation. The second area of interest is in hepatic and intestinal fatty acid metabolism. We are interested in lipid mobilization from enterocytes through chylomicron formation and in particular the regulation of cholesterol and triglyceride absorption. We have engineered novel strains of mice with tissue-specific deletion of genes responsible for fat mobilization and we are interested in their utility in targeted therapies for obesity and hypercholesterolemia. We are also interested in the molecular regulation of hepatic steatosis, in particular the gene-environment interactions that trigger insulin resistance, diet induced weight gain and hepatic lipid accumulation. In this area, we will employ both cell and animal models of altered fatty acid metabolism and extend the findings to studies in humans with obesity and hepatic steatosis, with the objective of identifying informative pathways that lead to steatosis and altered fatty acid utilization. SELECTED PUBLICATIONS Banerjee, B, Henderson, JO, Chaney, TC, and Davidson, NO. Detection of murine intestinal adenomas using targeted molecular autofluorescence. Dig. Dis. Sci. 2004. In Press. Newberry EP, Xie Y, Kennedy S, Han X, Buhman KK, Luo J, Gross RW, Davidson NO. Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene. J Biol Chem. 2003; 278 :51664-72. Blanc V, Kennedy S, Davidson NO. A novel nuclear localization signal in the auxiliary domain of apobec-1 complementation factor regulates nucleocytoplasmic import and shuttling. J Biol Chem. 2003; 278:41198-204. Xie Y, Nassir F, Luo J, Buhman K, Davidson NO. Intestinal lipoprotein assembly in apobec-1-/- mice reveals subtle alterations in triglyceride secretion coupled with a shift to larger lipoproteins. Am J Physiol Gastrointest Liver Physiol. 2003; 285:G735-46. |
