Proposed studies in this renewal application are directed at investigating the molecular pathophysiology of alcohol-induced end organ disease, especially as it relates to non-oxidative ethanol metabolism in extra-hepatic organs. Fatty acid ethyl ester synthases, discovered in myocardium in the laboratory of the principal investigator in 1981, catalyze the formation of fatty acid ethyl esters from ethanol. These lipids accumulate in human organs most commonly damaged by alcohol abuse, their rates of synthesis are greatest in these organs and they cause impairment of mitochondrial function, a hallmark of alcohol-induced end organ damage. Since many organs such as heart and pancreas lack oxidative metabolism of alcohol, this pathway may provide a crucial link between ethanol ingestion and genetic vulnerabilities found in alcohol-induced end-organ diseases, such as pancreatitis and cardiomyopathy. Proposed studies will focus on the biochemical characterization of the human pancreatic minor fatty acid ethyl ester synthase because the enzyme is now known to be present in the greatest amount in pancreas (Science 231:497, 1986) and because the minor synthase accounts for the majority of synthase activity. Its four molecular forms (200, 100, 67 and 52 kDa) will be all purified to homogeneity, characterized and protein sequences determined in part to allow use of recombinant DNA techniques. These will be employed to detect restriction fragment length polymorphisms, clone the synthases and provide chromosomal localization of their genes. The results directly relate to establishing molecular links in the pathophysiology of alcohol-induced end organ damage at the genetic level.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA006989-04
Application #
3110472
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1985-11-19
Project End
1991-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Barnes-Jewish Hospital
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110
Smith, C M; Bora, P S; Bora, N S et al. (1995) Genetic and radiation-reduced somatic cell hybrid sublocalization of the human GSTP1 gene. Cytogenet Cell Genet 71:235-9
Bello, A T; Bora, N S; Lange, L G et al. (1994) Cardioprotective effects of alcohol: mediation by human vascular alcohol dehydrogenase. Biochem Biophys Res Commun 203:1858-64
Bora, P S; Bora, N S; Wu, X et al. (1994) Molecular cloning, sequencing, and characterization of smooth muscle myosin alkali light chain from human eye cDNA: homology with myocardial fatty acid ethyl ester synthase-III cDNA. Genomics 19:186-8
Bora, P S; Lange, L G (1993) Molecular mechanism of ethanol metabolism by human brain to fatty acid ethyl esters. Alcohol Clin Exp Res 17:28-30
Isenberg, K E; Bora, P S; Zhou, X et al. (1992) Nonoxidative ethanol metabolism: expression of fatty acid ethyl ester synthase-III in cultured neural cells. Biochem Biophys Res Commun 185:938-43
Bora, P S; Wu, X; Lange, L G (1992) Site-specific mutagenesis of two histidine residues in fatty acid ethyl ester synthase-III. Biochem Biophys Res Commun 184:706-11
Bora, P S; Wu, X; Spilburg, C A et al. (1992) Purification and characterization of fatty acid ethyl ester synthase-II from human myocardium. J Biol Chem 267:13217-21
Bora, P S; Bora, N S; Wu, X L et al. (1991) Molecular cloning, sequencing, and expression of human myocardial fatty acid ethyl ester synthase-III cDNA. J Biol Chem 266:16774-7
Gulick, T; Pieper, S J; Murphy, M A et al. (1991) A new method for assessment of cultured cardiac myocyte contractility detects immune factor-mediated inhibition of beta-adrenergic responses. Circulation 84:313-21
Kinnunen, P M; Klopf, F H; Bastiani, C A et al. (1990) 12-[(5-iodo-4-azido-2-hydroxybenzoyl)amino]dodecanoic acid: biological recognition by cholesterol esterase and acyl-CoA:cholesterol O-acyltransferase. Biochemistry 29:1648-54

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