Project 2 will use functional toxicogenomics and proteomics technologies to uncover the genes and pathways that determine cellular responses and genetic susceptibilities to arsenic, cadmium, chromium, nickel and other heavy metals that contaminate Superfund sites. Comparative functional genomics will provide key insights into some of the basic mechanisms that determine resistance or sensitivity to heavy metal toxicants. These studies are divided into three Specific Aims: 1) Assemble a functional genomic profile of fission yeast using a panel of environmental toxicants assessed with haploid and diploid deletion libraries. Barcode analysis determined by deep sequencing will provide a detailed and quantitative picture of the genes that determine susceptibilities to heavy metals. Cluster analysis will be applied to toxicants tested in pure forms or in mixtures. 2) Build on the functional genomic profiling data by assembling epistatic miniarray profiles (E-MAPs). These mutant interaction studies will define the genetic networks that determine cellular sensitivities to heavy metals and may uncover interactions with other pathways such as DNA damage responses (DDRs). The existence of conserved genetic interactions in human cells will be assessed by RNAi analyses. 3) Investigate changes in protein abundance triggered by heavy metal exposure using isobaric tag for relative and absolute quantitation (iTRAQ). These proteomic studies will provide further insights into how stress-regulated transcription factors and stress-activated protein kinases control cellular responses to heavy metal stress.

Public Health Relevance

Genetic variation of multiple loci likely determines individual susceptibilities to mixtures of toxicants found at Superfund sites. Functional toxicogenomics will be used to define the genes and genetic interactions that determine heavy metal sensitivity in fission yeast. Insights gleaned from these studies will be applied to investigating the effects of heavy metals in human cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES010337-12
Application #
8463198
Study Section
Special Emphasis Panel (ZES1-JAB-J)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
12
Fiscal Year
2013
Total Cost
$299,274
Indirect Cost
$10,826
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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