This proposal describes genetic and biochemical studies that are aimed at developing a better understanding of the effects of hazardous chemicals on eukaryotic organisms. The investigators want to decipher how eukaryotes sense hazardous chemicals and how they mount defensive responses. A central aim of these studies is to understand the signal transduction mechanisms that control gene expression in response to exposure to toxic chemicals. This type of knowledge will be crucial for understanding the effects of toxic chemicals on human health. A critical long-term goal of these studies will be the development of new strategies to improve detection of environmental toxins. Arsenic and cadmium will be emphasized in these investigations, although hydrogen peroxide will also be used as an efficient and specific method of inflicting oxidative stress. The fission yeast Schizosaccharomyces pombe will be used as the experimental organism for these studies. Fission yeast has be valuable model system for studying basic features of genotoxic and cytotoxic stress response mechanisms that are conserved amongst most eukaryotes, including mammals and plants. In the last funding period the investigators identified Csxl, a novel RNA-binding protein that controls global patterns of gene expression in response to oxidative stress In the upcoming funding period we propose to further these studies and to expand our area of investigation to include a functional genomics screen of genes whose expression is regulated in response to cadmium and arsenic exposure. They also plan to develop yeast strains that have arsenic and cadmium induced genes fused to readily detectable biomarkers. The project has three Specific Aims: 1) to understand how Csxl controls gene expression in response to oxidative stress. Csxl controls mRNA turnover during oxidative stress. All the mRNAs will be defined that are directly regulated by Csxl and investigate Cip1 and Cip2, two Csxl-interacting proteins. that play important roles in controlling gene expression in response to oxidative stress. The other Specific Aims are to 2) carry out a functional genomics screen to identify novel genes that play significant roles in tolerance of cadmium and arsenic, and 3) develop specific biomarkers for arsenic and cadmium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES010337-10
Application #
7799233
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
10
Fiscal Year
2009
Total Cost
$303,017
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Brouha, Sharon S; Nguyen, Phirum; Bettencourt, Ricki et al. (2018) Increased severity of liver fat content and liver fibrosis in non-alcoholic fatty liver disease correlate with epicardial fat volume in type 2 diabetes: A prospective study. Eur Radiol 28:1345-1355
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

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