This is a request for an ADAMHA RSDA (Level II). Alcohol dehydrogenase (ADH) is the rate-limiting step in the oxidation of alcohol by mammals. ADH gene expression occurs primarily in the liver where it serves a major detoxification function. Since human ADH shows a strong preference for expression in the liver, it is of great interest to my laboratory to study the mechanism of this tissue-specificity. In addition, glucocorticoids have been reported to regulate liver ADH gene expression, and preliminary studies in this lab indicate a direct effect of glucocorticoids on transcription. Regulation at the level of transcription initiation will be analyzed in detail to ascertain the cis- acting DNA elements and ultimately the trans-acting protein factors necessary to produce the high level of ADH gene expression seen in liver. The involvement of glucocorticoids in regulating ADH transcription will be analyzed in further detail. This knowledge will be important for understanding the overall effects of alcohol abuse and alcoholism upon humans since the ability of individuals to induce liver ADH levels during times of ethanol-induced stress may play a role in determining the extent to which they suffer from this disease. The broader benefit of these biochemical studies is that it will provide information which will further our general understanding of mammalian transcriptional regulation, a process which is ill understood. The ADH project is just coming to fruit right now and promises to provide a wealth of information on liver-specific transcriptional regulation and alcohol metabolism in the liver. A five-year RSDA (Level II) fits perfectly into my scientific career development. Since taking the position at colorado state University I have encountered other responsibilities, primarily teaching, which divert my attention from research. An RSDA would help reduce the teaching burden and allow me to more fully focus my energy to the ADH research project which is becoming increasingly more complex. Such an award would allow me to spend more time in the lab myself, a task which I have been trained to perform very efficiently and which is very rewarding personally. It would also increase the amount of time I can spend developing collaborative relationships with other laboratories in order to learn new techniques and develop new ideas.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AA000119-03
Application #
3069341
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1989-09-01
Project End
1991-12-31
Budget Start
1991-09-01
Budget End
1991-12-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Type
Schools of Arts and Sciences
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Zgombic, M; Duester, G (1993) DNA elements mediating retinoid and thyroid hormone regulation of alcohol dehydrogenase gene expression. Adv Exp Med Biol 328:571-80
Shean, M L; Duester, G (1993) The role of alcohol dehydrogenase in retinoic acid homeostasis and fetal alcohol syndrome. Alcohol Alcohol Suppl 2:51-6
van Ooij, C; Snyder, R C; Paeper, B W et al. (1992) Temporal expression of the human alcohol dehydrogenase gene family during liver development correlates with differential promoter activation by hepatocyte nuclear factor 1, CCAAT/enhancer-binding protein alpha, liver activator protein, and D-element-bindi Mol Cell Biol 12:3023-31
Harding, P P; Duester, G (1992) Retinoic acid activation and thyroid hormone repression of the human alcohol dehydrogenase gene ADH3. J Biol Chem 267:14145-50
Duester, G; Shean, M L; McBride, M S et al. (1991) Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis. Mol Cell Biol 11:1638-46
Stewart, M J; Shean, M L; Paeper, B W et al. (1991) The role of CCAAT/enhancer-binding protein in the differential transcriptional regulation of a family of human liver alcohol dehydrogenase genes. J Biol Chem 266:11594-603
Duester, G (1991) A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step. Alcohol Clin Exp Res 15:568-72
Stewart, M J; Shean, M L; Duester, G (1990) trans activation of human alcohol dehydrogenase gene expression in hepatoma cells by C/EBP molecules bound in a novel arrangement just 5' and 3' to the TATA box. Mol Cell Biol 10:5007-10
Stewart, M J; McBride, M S; Winter, L A et al. (1990) Promoters for the human alcohol dehydrogenase genes ADH1, ADH2, and ADH3: interaction of CCAAT/enhancer-binding protein with elements flanking the ADH2 TATA box. Gene 90:271-9
Winter, L A; Stewart, M J; Shean, M L et al. (1990) A hormone response element upstream from the human alcohol dehydrogenase gene ADH2 consists of three tandem glucocorticoid receptor binding sites. Gene 91:233-40