The objectives of the proposed studies are two-fold: 1) To investigate the mechanisms of the effects of hormones on the regulation of rat class I alcohol dehydrogenase. These studies include characterization of trans-acting factors that regulate expression of the gene, and determination of the mechanisms whereby hormones affect transcription of the gene. 2) To study mechanisms whereby acetaldehyde, the product of ethanol oxidation by alcohol dehydrogenase, stimulates fibrogenesis. These studies are focused on identifying trans-acting factors that regulate expression of the type I collagen genes, and determining whether the effect of acetaldehyde is mediated by modification of the amounts or binding affinity of these trans-acting factors to the collagen genes. Growth hormone (GH) increases alcohol dehydrogenase by increasing its synthesis at the level of transcription, while dihydrotestosterone decreases alcohol dehydrogenase by increasing its rate of degradation. It will now be determined whether the effect of GH in enhancing transcription (STAT) proteins. The pathway for degradation of alcohol dehydrogenase will be defined by determining if specific inhibitors of various pathways prevent the effect of dihydrotestosterone in increasing degradation of the enzyme. Mechanisms for the effects of acetaldehyde in enhancing collagen formation will be studied in cultured hepatic stellate cells. The role of retinoic acid (RA), retinoic acid receptors and their binding to RA-responsive elements (RARE) in the (1(I) collagen promoters will be assessed as mediators for the acetaldehyde. The role of C/EBP-beta for basal activity and for the activation of the alpha1 (I) collagen promoter by acetaldehyde will be determined in transfection experiments with the wild type and promoter mutated at the C/EBP-beta binding site and with co-transfection with a C/EBP-beta expression vector. The mechanism whereby acetaldehyde increases nuclear C/EBP-beta protein and binding to the collagen promoter will be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA000626-27
Application #
6371259
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Russo, Denise A
Project Start
1977-06-01
Project End
2005-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
27
Fiscal Year
2001
Total Cost
$327,000
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Altszuler, Amy R; Page, Timothy F; Gnagy, Elizabeth M et al. (2016) Financial Dependence of Young Adults with Childhood ADHD. J Abnorm Child Psychol 44:1217-29
Molina, Brooke S G; Gnagy, Elizabeth M; Joseph, Heather M et al. (2016) Antisocial Alcoholism in Parents of Adolescents and Young Adults With Childhood ADHD. J Atten Disord :
Babinski, Dara E; Pelham Jr, William E; Molina, Brooke S G et al. (2016) Maternal ADHD, Parenting, and Psychopathology Among Mothers of Adolescents With ADHD. J Atten Disord 20:458-68
Kuriyan, Aparajita B; Pelham Jr, William E; Molina, Brooke S G et al. (2014) Concordance between parent and physician medication histories for children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 24:269-74
Babinski, Dara E; Sibley, Margaret H; Ross, J Megan et al. (2013) The effects of single versus mixed gender treatment for adolescent girls with ADHD. J Clin Child Adolesc Psychol 42:243-50
Kuriyan, Aparajita B; Pelham Jr, William E; Molina, Brooke S G et al. (2013) Young adult educational and vocational outcomes of children diagnosed with ADHD. J Abnorm Child Psychol 41:27-41
Potter, James J; Liu, Xiaopu; Koteish, Ayman et al. (2013) 1,25-dihydroxyvitamin D3 and its nuclear receptor repress human ýý1 (I) collagen expression and type I collagen formation. Liver Int 33:677-86
An, Fangmei; Yamanaka, Sumitaka; Allen, Sarah et al. (2012) Silencing of miR-370 in human cholangiocarcinoma by allelic loss and interleukin-6 induced maternal to paternal epigenotype switch. PLoS One 7:e45606
Sibley, Margaret H; Pelham, William E; Molina, Brooke S G et al. (2012) Diagnosing ADHD in adolescence. J Consult Clin Psychol 80:139-150
Babinski, Dara E; Pelham Jr, William E; Molina, Brooke S G et al. (2011) Women with Childhood ADHD: Comparisons by Diagnostic Group and Gender. J Psychopathol Behav Assess 33:420-429

Showing the most recent 10 out of 99 publications