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.
|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|
|Karmakar, Saswata; Guenther, Dale C; Gibbons, Bradley C et al. (2017) Recognition of mixed-sequence DNA using double-stranded probes with interstrand zipper arrangements of O2'-triphenylene- and coronene-functionalized RNA monomers. Org Biomol Chem 15:9362-9371|
|Simmons, Aaron B; Bloomsburg, Samuel J; Sukeena, Joshua M et al. (2017) DSCAM-mediated control of dendritic and axonal arbor outgrowth enforces tiling and inhibits synaptic plasticity. Proc Natl Acad Sci U S A 114:E10224-E10233|
|Marx, Hannah E; Dentant, Cédric; Renaud, Julien et al. (2017) Riders in the sky (islands): using a mega-phylogenetic approach to understand plant species distribution and coexistence at the altitudinal limits of angiosperm plant life. J Biogeogr 44:2618-2630|
|Olson, Xiaoping; Kotani, Shohei; Padilla, Jennifer E et al. (2017) Availability: A Metric for Nucleic Acid Strand Displacement Systems. ACS Synth Biol 6:84-93|
|Yano, Hirokazu; Wegrzyn, Katarznya; Loftie-Eaton, Wesley et al. (2016) Evolved plasmid-host interactions reduce plasmid interference cost. Mol Microbiol 101:743-56|
|Gunderson, Mark P; Pickett, Melissa A; Martin, Justin T et al. (2016) Variations in hepatic biomarkers in American alligators (Alligator mississippiensis) from three sites in Florida, USA. Chemosphere 155:180-187|
|Aldape, Michael J; Bayer, Clifford R; Bryant, Amy E et al. (2016) A novel murine model of Clostridium sordellii myonecrosis: Insights into the pathogenesis of disease. Anaerobe 38:103-110|
|Simmons, Aaron B; Bloomsburg, Samuel J; Billingslea, Samuel A et al. (2016) Pou4f2 knock-in Cre mouse: A multifaceted genetic tool for vision researchers. Mol Vis 22:705-17|
|Fernandes, K A; Bloomsburg, S J; Miller, C J et al. (2016) Novel axon projection after stress and degeneration in the Dscam mutant retina. Mol Cell Neurosci 71:1-12|
Showing the most recent 10 out of 466 publications