The goal of this application Is to maintain transgenic knockout animal models that are unique and have high relevance to alcohol research. Alcohol-induced toxicity commonly Involves oxidative stress. Ethanol metabolism by microsomal and mitochondrial systems generates reactive oxygen species and reactive nitrogen species, and is associated with diminished glutathione (GSH) and antioxidant enzymatic activity. In addition, the accumulation of ethanol-derived aldehydes and hydroxyethyl radical serves to modify critical biological functions by forming adducts with proteins and DNA. The availability of animal models in which ethanol metabolism or antioxidant mechanisms are genetically modified will facilitate investigation of the role these enzymes and oxidative stress In diseases associated with ethanol consumption. Therefore, we propose:
Specific Aim 1 : To maintain the populations of existing mouse models in our laboratory so that they are readily available to researchers. Our current models include: a) the conventlonal7 /c(/77af, Aldhlbl, Aldh2, Cat, Cyp2e1, Adhi and Gclm single knockouts, b) the Cat/Cyp2e1 double knockout, and c) the hepatocyte-specific Gclc^^ knockout and the conditional Gclc '^floxed strain.
Specific Aim 2 : To generate (and maintain) unique additional mouse knockout models so that they are readily available to researchers. These Include: a) Cyp2e1/Adh1, Cat/Cyp2e1, Cat/Adhi and Cat/Cyp2e1/Adh1 triple knockout, b) Aldhlal/Aldhlbl, Aldh1b1/Aldh2 and the Aldh1a1/Aldh1b1/Aldh2 triple knockout strains, and c) Gclm/Cyp2e1 and Gclm/Aldhlal double knockout strains. Our overarching aim Is to make valuable transgenic animal models available to the larger research community. It is expected that enhanced access to such models will accelerate our understanding of the mechanisms underlying alcohol-Induced disease and the pathophysiological effects of acute and chronic alcohol consumption. Such knowledge would facilitate the development of more effective treatments of alcohol abuse.
Alcohol-Induced toxicity is associated with oxidative stress resulting from ethanol metabolism that generates reactive oxygen species and Is associated with reduced glutathione (GSH). The goal of this application Is to maintain and expand animal models with genetic defects In alcohol metabolizing enzymes and In GSH synthesizing enzymes that will become available to the research community.
|Yang, Shyh-Ming; Martinez, Natalia J; Yasgar, Adam et al. (2018) Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity. J Med Chem 61:4883-4903|
|Rattray, Nicholas J W; Deziel, Nicole C; Wallach, Joshua D et al. (2018) Beyond genomics: understanding exposotypes through metabolomics. Hum Genomics 12:4|
|Lian, Gaojian; Gnanaprakasam, Jn Rashida; Wang, Tingting et al. (2018) Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation. Elife 7:|
|Matsumoto, Akiko; Arcaroli, John; Chen, Ying et al. (2017) Aldehyde dehydrogenase 1B1: a novel immunohistological marker for colorectal cancer. Br J Cancer 117:1537-1543|
|Johnson, Caroline H; Athersuch, Toby J; Collman, Gwen W et al. (2017) Yale school of public health symposium on lifetime exposures and human health: the exposome; summary and future reflections. Hum Genomics 11:32|
|Mak, Tak W; Grusdat, Melanie; Duncan, Gordon S et al. (2017) Glutathione Primes T Cell Metabolism for Inflammation. Immunity 46:1089-1090|
|Rattray, Nicholas J W; Charkoftaki, Georgia; Rattray, Zahra et al. (2017) Environmental influences in the etiology of colorectal cancer: the premise of metabolomics. Curr Pharmacol Rep 3:114-125|
|Chen, Ying; Singh, Surendra; Matsumoto, Akiko et al. (2016) Chronic Glutathione Depletion Confers Protection against Alcohol-induced Steatosis: Implication for Redox Activation of AMP-activated Protein Kinase Pathway. Sci Rep 6:29743|
|Heit, Claire; Eriksson, Peter; Thompson, David C et al. (2016) Quantification of Neural Ethanol and Acetaldehyde Using Headspace GC-MS. Alcohol Clin Exp Res 40:1825-31|
|Singh, Surendra; Arcaroli, John J; Orlicky, David J et al. (2016) Aldehyde Dehydrogenase 1B1 as a Modulator of Pancreatic Adenocarcinoma. Pancreas 45:117-22|
Showing the most recent 10 out of 27 publications