The long term objective of this research is to elucidate and characterize the mechanisms responsible for tissue-specific differential gene expression using the rat Class 3 aldehyde dehydrogenase gene (ALDH-3) as the model system. The mammalian ALDH-3 gene exhibits several aspects of tissue-specific gene expression. Certain normal tissues such as the cornea constitutively express Class-3 ALDH at very high levels. Other tissues such as normal liver express no Class-3 ALDH. In liver induction of Class 3 ALDH activity occurs following both xenobiotic exposure (to TCDD or 3- rnethylcholantherene) and during hepatocarcinogenesis. All evidence indicates both constitutive and inducible regulation of the ALDH 3 gene occurs at the transcriptional level and involves differential use of both cis-acting elements and trans-acting factors. The specific aims of this proposal are :( l) Complete fine-structure analysis of regulation of the ALDH3 gene in liver and hepatoma cells; (2) Compare regulation of ALDH-3 gene expression in a constitutively expressing tissue, the cornea, to that of liver; (3) Continue assessing physiological roles of Class 3 ALDH in the metabolism of aldehydes generated by cellular oxidative stress. Completion of these specific aims will allow us to understand the molecular basis of differential gene expression under both normal and pathophysiological conditions. The results will, in turn, provide insights into how differential gene expression is related to the physiological role of the gene product.