• Name: Jennifer R. Chase, Ph.D.
  • Institution: Northwest Nazarene University
  • Department: Biology
  • Phone: 208-467-8892
  • Email: jrchase@nnu.edu

Summary: Changes in retinoic acid (RA) levels have been implicated in the development of alcohol-related cancers in chronic heavy drinkers and in fetal alcohol syndrome. RA is synthesized in a two step pathway that must produce RA in the proper temporal and spatial pattern to cause or maintain proper cellular differentiation. In vitro, alcohol is a competitive inhibitor of retinol for oxidation by human ADHs. . It is reasonable to infer that decreased RA synthesis by this pathway is a mechanism by which alcohol causes disease. However, some animal studies show the opposite effect. Because in vivo human experiments cannot be performed, an accurate model to study the relationship between RA production and alcohol is needed. Our project includes purifying and measuring the kinetic constants for human alcohol dehydrogenases and aldehyde dehydrogenases that are the first step in the synthesis of retinoic acid from retinol (vitamin A). These values are then used to make a mathematical model of retinoic acid metabolism via the enzymes alcohol and aldehyde dehydrogenases. The computational model can be used to assess the degree that genetic makeup and alcohol alter the synthesis of retinoic acid and, thereby, promote human disease.

Minimum Classes: General Chemistry and labs (1 year), Introductory Cell and Molecular Biology and labs (1st semester).

Projects: 1. Human enzyme purification & assays Students will use bacterial culture techniques, centrifugation, and affinity or ion exchange chromatography to isolate human alcohol dehydrogenase from bacterial clones. The purified enzyme will be assayed using spectrophotometry, to determine binding and rate constants for the enzyme as well as to determine the rate of the reactions under physiological conditions. Students should have studied general chemistry and general biology, at least. The purpose of this part of the project is to both (a) measure required kinetic constants under appropriate conditions to match in vivo conditions. Not only will this augment the literature but it will provide these values for the computational model. 2. Computational modeling: Students will assemble computational models to calculate the effect of ethanol on its own or the oxidation of retinol. Using constants gleaned from the literature or obtained in our lab, students will modify existing computational models to evaluate the effect of additional enzymes or change in values. These models use large (but straight-forward) equations to describe the rate of the ethanol or retinol oxidation in the presence of physiological inhibitors. Individual enzyme models already exist but students would be combining these and optimizing them for physiological conditions. An ideal student would have some programming experience and have studied biochemistry. The purpose of this part of the project is to assess the hypothesized role of ethanol in altering RA production in human tissues.

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