The premise of the UCSD SBRP states that a toxic episode resulting from exposure to environmental toxicants stems from altered gene control. Activation of the dioxin or AhR plays an important role in the coordination of selective cellular events that lead to bioactivation of toxicants through Phase I cytochrome P450 (CYP)-dependent mechanisms while assuring appropriate cellular protection by induction of Phase II UGT1 glucuronidation pathways. During the past funding period, our laboratory has characterized the full length human CYP1A1 gene as well as the UGT1 locus. To understand the contribution of these genes in defining a toxic event following activation of the AhR, we have developed transgenic mouse lines that carry and express the entire human CYP1A1 gene and the UGT1 locus. With an emphasis in the UCSD SBRP to develop models that can used to identify toxicants, novel mouse strains are being designed that express detectable CYP1A1 or UGT1 luminescent and fluorescent markers that are induced in response to toxicants that activate the AhR. In addition, experiments have been initiated in this application using resources available through the Superfund Core services to .humanize. the CYP1A1 gene and the UGT1 locus in mice with the intention that we will gain valuable insight into the regulatory and humoral responses that link expression of these genes to toxicity. During the course of these studies, it is anticipated that a number of significant biological tools will be developed that can be utilized as biomarkers or resources to examine the contribution of AhR directed toxicants toward gene activation and toxicity. These resources will be exploited by the Research Translation Core and used by this program to determine the feasibility of applying these biological tools as biomarkers for the detection of selective environmental toxicants. The investigators are hopeful that these efforts and future collaborations will further an understanding for the role of the AhR in toxicant induced illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES010337-09
Application #
7598925
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
9
Fiscal Year
2008
Total Cost
$256,148
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Hsu, Po-Kai; Takahashi, Yohei; Munemasa, Shintaro et al. (2018) Abscisic acid-independent stomatal CO2 signal transduction pathway and convergence of CO2 and ABA signaling downstream of OST1 kinase. Proc Natl Acad Sci U S A 115:E9971-E9980
Dhar, Debanjan; Antonucci, Laura; Nakagawa, Hayato et al. (2018) Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling. Cancer Cell 33:1061-1077.e6
Febbraio, Mark A; Reibe, Saskia; Shalapour, Shabnam et al. (2018) Preclinical Models for Studying NASH-Driven HCC: How Useful Are They? Cell Metab :
Fujiwara, Ryoichi; Yoda, Emiko; Tukey, Robert H (2018) Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans. Drug Metab Pharmacokinet 33:9-16
Hartmann, Phillipp; Hochrath, Katrin; Horvath, Angela et al. (2018) Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. Hepatology 67:2150-2166
Ganguly, Abantika; Guo, Lan; Sun, Lingling et al. (2018) Tdp1 processes chromate-induced single-strand DNA breaks that collapse replication forks. PLoS Genet 14:e1007595
Tripathi, Anupriya; Debelius, Justine; Brenner, David A et al. (2018) The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 15:397-411
Chen, Shujuan; Tukey, Robert H (2018) Humanized UGT1 Mice, Regulation of UGT1A1, and the Role of the Intestinal Tract in Neonatal Hyperbilirubinemia and Breast Milk-Induced Jaundice. Drug Metab Dispos 46:1745-1755
Desai, Archita P; Mohan, Prashanthinie; Roubal, Anne M et al. (2018) Geographic Variability in Liver Disease-Related Mortality Rates in the United States. Am J Med 131:728-734
Ajmera, Veeral; Park, Charlie C; Caussy, Cyrielle et al. (2018) Magnetic Resonance Imaging Proton Density Fat Fraction Associates With Progression of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 155:307-310.e2

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