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 as the model system.
The Specific Aims of this proposal are: (1) To complete characterization of the class 3 aldehyde dehydrogenase gene. (2) Compare organization of class 3 aldehyde dehydrogenase gene to that of mitochondrial and microsomal aldehyde dehydrogenase. (3) To determine the role of DNA methylation in class 3 aldehyde dehydrogenase gene expression. (4) To analyse the role of DNA-protein interactions in the regulation of class 3 aldehyde dehydrogenase gene expression. (5) To continue testing the hypothesis that a major physiological role for the class 3 aldehyde dehydrogenase in both neoplastic and normal cells is the oxidation of aldehydes generated from lipid peroxidation. By completing the Specific Aims outlined above, we will have completed the first detailed molecular analysis of the structural and functional organization of a gene which (a) differs in constitutive expression in normal tissues; (b) is differentially inducible in normal tissues; and (c) is differentially expressed in diseased tissues. We will also have clearly defined the mechanisms involved in these changes in expression. Lastly, we will have demonstrated how differential gene expression is related to the physiological role of the gene product.
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