Our long-term goal is to prevent liver cancer by eliminating dietary aflatoxin and human exposure to this mycotoxin in food. In past research, we made significant progress towards this long-term goal and accomplished two short-term goals. (1) We identified key components in the genetic switch that activate aflatoxin gene expression and developed a comprehensive model that predicts the detailed mechanisms by which the switch regulates the timing and level of aflatoxin synthesis. (2) We identified several fungal and plant metabolites that block aflatoxin accumulation and gene expression. In the next phase of this research, we will analyze two key components of the switch mechanism in sufficient detail to identify specific steps that are susceptible to control. Using this information, we will continue to identify and test promising natural plant and fungal compounds that block aflatoxin synthesis. This research approach will allow us to confirm or modify key steps in the regulatory model and will fill a critical knowledge gap in our understanding of aflatoxin synthesis specifically and in control of complex gene clusters in general. This approach will also assist efforts to formulate and apply effective strategies to block aflatoxin synthesis on susceptible crops. Based on our model of the genetic switch, we present two central hypotheses: 1) active CRE1bp complexes recruit proteins necessary for initiation of aflatoxin gene expression (AflR and HAT);2) the timing and level of aflatoxin gene activation is in part controlled by the initiation and spread of histone H4 acetylation in the aflatoxin gene cluster. To address these hypotheses, we propose to accomplish two Specific Aims. 1. Analyze the role of CRE1bp in aflatoxin gene activation. 2. Analyze the role of histone H4 acetylation in aflatoxin gene activation. As part of the proposed work for each specific aim, we will identify new inhibitors of aflatoxin synthesis and determine the specific mechanisms by which these and previously identified inhibitors block aflatoxin synthesis. Our work will allow us to effectively control aflatoxin synthesis on food and feed crops - this outcome will have a large positive impact on human health by providing one practical strategy to reduce liver cancer incidence.

Public Health Relevance

As part of the proposed work, we will identify new inhibitors of aflatoxin synthesis and determine the specific mechanisms by which these and previously identified inhibitors block aflatoxin synthesis. Our work will allow us to effectively control aflatoxin synthesis on food and feed crops. This outcome will have a large positive impact on human health by providing one practical strategy to reduce liver cancer incidence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA052003-21
Application #
8255601
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Johnson, Ronald L
Project Start
1991-01-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
21
Fiscal Year
2012
Total Cost
$206,479
Indirect Cost
$64,753
Name
Michigan State University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Wee, Josephine; Day, Devin M; Linz, John E (2016) Effects of Zinc Chelators on Aflatoxin Production in Aspergillus parasiticus. Toxins (Basel) 8:
Roze, Ludmila V; Laivenieks, Maris; Hong, Sung-Yong et al. (2015) Aflatoxin biosynthesis is a novel source of reactive oxygen species--a potential redox signal to initiate resistance to oxidative stress? Toxins (Basel) 7:1411-30
Linz, John E; Wee, Josephine; Roze, Ludmila V (2014) Aspergillus parasiticus SU-1 genome sequence, predicted chromosome structure, and comparative gene expression under aflatoxin-inducing conditions: evidence that differential expression contributes to species phenotype. Eukaryot Cell 13:1113-23
Hong, Sung-Yong; Roze, Ludmila V; Wee, Josephine et al. (2013) Evidence that a transcription factor regulatory network coordinates oxidative stress response and secondary metabolism in aspergilli. Microbiologyopen 2:144-60
Ehrlich, Kenneth C; Mack, Brian M; Wei, Qijian et al. (2012) Association with AflR in endosomes reveals new functions for AflJ in aflatoxin biosynthesis. Toxins (Basel) 4:1582-1600
Linz, John E; Chanda, Anindya; Hong, Sung-Yong et al. (2012) Proteomic and biochemical evidence support a role for transport vesicles and endosomes in stress response and secondary metabolism in aspergillus parasiticus. J Proteome Res 11:767-75
Roze, Ludmila V; Beaudry, Randolph M; Linz, John E (2012) Analysis of volatile compounds emitted by filamentous fungi using solid-phase microextraction-gas chromatography/mass spectrometry. Methods Mol Biol 944:133-42
Roze, Ludmila V; Chanda, Anindya; Linz, John E (2011) Compartmentalization and molecular traffic in secondary metabolism: a new understanding of established cellular processes. Fungal Genet Biol 48:35-48
Roze, Ludmila V; Chanda, Anindya; Wee, Josephine et al. (2011) Stress-related transcription factor AtfB integrates secondary metabolism with oxidative stress response in aspergilli. J Biol Chem 286:35137-48
Roze, Ludmila V; Koptina, Anna V; Laivenieks, Maris et al. (2011) Willow volatiles influence growth, development, and secondary metabolism in Aspergillus parasiticus. Appl Microbiol Biotechnol 92:359-70

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