This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Alcoholism and alcohol abuse are significant public concerns, leading to fetal alcohol syndrome, liver cirrhosis and aerodigestive cancers. It is hypothesized that one mechanism by which alcoholism leads to these diseases is via disruption of homeostasis of the potent cell-signaling molecule, retinoic acid. Currently there is no comprehensive model of retinol-related pathways, nor their dysregulation in liver disease. As a consequence there is considerable debate about which enzymes on the pathway of retinol to retinoic acid are significant in vivo and which are affected by ethanol or its metabolites, and to what degree. We hypothesize that the ethanol-induced increases in NADH and acetaldehyde (Ach) significantly inhibit retinoic acid synthesis in human liver cells by inhibition of aldehyde and alcohol dehydrogenases.
In specific Aim 1 we will computationally model the effect of ethanol-induced changes in NADH and Ach on retinol oxidation by ADH isoforms.
In Specific Aim 2 we will measure in vitro retinol oxidation kinetics of recADH1 and 7 isoforms, in the presence of Ach and NADH levels to match the computational parameters.
In Specific Aim 3 we will assess the impact of elevated NADH and Ach on retinol oxidation by HeLa-ADH1B, and HeLa-ADH1B-ALDH2 cells. Finally, in Specific Aim 4 we will design a computational model of the retinol metabolic pathways present in human hepatic stellate cells. Results from these studies will enable us to develop a better model for the role of the cell-signaling model retinoic acid in normal liver function and its disruption in alcohol-related disease.
|Tawara, Ken; Bolin, Celeste; Koncinsky, Jordan et al. (2018) OSM potentiates preintravasation events, increases CTC counts, and promotes breast cancer metastasis to the lung. Breast Cancer Res 20:53|
|Boursier, Michelle E; Moore, Joseph D; Heitman, Katherine M et al. (2018) Structure-Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR. ACS Chem Biol 13:2655-2662|
|Culbertson, Vaughn L; Rahman, Shaikh E; Bosen, Grayson C et al. (2018) Implications of Off-Target Serotoninergic Drug Activity: An Analysis of Serotonin Syndrome Reports Using a Systematic Bioinformatics Approach. Pharmacotherapy 38:888-898|
|Gunderson, Mark P; Nguyen, Brandon T; Cervantes Reyes, Juan C et al. (2018) Response of phase I and II detoxification enzymes, glutathione, metallothionein and acetylcholine esterase to mercury and dimethoate in signal crayfish (Pacifastacus leniusculus). Chemosphere 208:749-756|
|Ruffley, Megan; Smith, Megan L; Espíndola, Anahí et al. (2018) Combining allele frequency and tree-based approaches improves phylogeographic inference from natural history collections. Mol Ecol 27:1012-1024|
|Nhu Lam, Mila; Dudekula, Dastagiri; Durham, Bri et al. (2018) Insights into ?-ketoacyl-chain recognition for ?-ketoacyl-ACP utilizing AHL synthases. Chem Commun (Camb) 54:8838-8841|
|McGinn, Timothy E; Mitchell, Diana M; Meighan, Peter C et al. (2018) Restoration of Dendritic Complexity, Functional Connectivity, and Diversity of Regenerated Retinal Bipolar Neurons in Adult Zebrafish. J Neurosci 38:120-136|
|LaFoya, Bryce; Munroe, Jordan A; Pu, Xinzhu et al. (2018) Src kinase phosphorylates Notch1 to inhibit MAML binding. Sci Rep 8:15515|
|Sun, Chi; Galicia, Carlos; Stenkamp, Deborah L (2018) Transcripts within rod photoreceptors of the Zebrafish retina. BMC Genomics 19:127|
|Bowman, Kole; Rose, Jack (2017) Estradiol stimulates glycogen synthesis whereas progesterone promotes glycogen catabolism in the uterus of the American mink (Neovison vison). Anim Sci J 88:45-54|
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