UNC Researchers Awarded a $2.6 Million NIH Grant to Apply Systems Biology Approaches to Studies of Liver Toxicity

Ivan RusynIvan Rusyn, M.D., Ph.D., Assistant Professor of Environmental Sciences and Engineering, and David Threadgill, Ph.D., Associate Professor of Genetics, received a 5-year award entitled Metabolomic and Toxicogenetic Study of Ethanol Toxicity from the National Institute of Alcohol Abuse and Alcoholism (NIAAA). This successful application combines metabolomics and mouse models in a new systems biology approach for molecular dissection and discovery of biological pathways underlying susceptibility to ethanol-induced liver injury. The UNC-Chapel Hill-based team of investigators, that also includes Michael Wheeler, Ph.D., Assistant Professor of Nutrition, and Steven Marron, Ph.D., Professor of Statistics and Operations Research, will test the hypothesis that by combining a state-of-the-art in vivo model of liver toxicity, a prior knowledge of the mechanisms of ethanol-induced liver injury, novel metabolic, genomic and pathologic analyses with genetic diversity of mouse inbred strains, it is possible to define a "liver toxicity susceptibility state."


"Integration of novel multi-dimensional data types, such as those provided by metabolomics, gene expression profiling, and genetics, with standard markers for evaluation of organ-specific toxicity, and available knowledgebases on the mechanisms of environmental agent-induced organ injury holds great promise," says Dr. Ivan Rusyn, a Principal Investigator of this proposal. A set of inbred mouse strains will be used in these studies. "The unique characteristics of the laboratory mouse and its central role as a model organism in biomedical research make this a logical choice for testing new approaches to the advancement of environmental health research," adds Dr. David Threadgill, a co-Principal Investigator. "Inbred mouse strains represent fixed, renewable genotypes ideally suited for whole genome approaches to define unique signatures associated with biological responses to toxicant exposure. Likewise, the diversity of genotypes archived in different inbred mouse strains is ideally suited to identify and dissect genotype-specific responses to toxicant exposure."


Both Rusyn and Threadgill agree that this proposal would not be possible without a unique collaborative spirit of research that exists at Carolina and is facilitated by several inter-disciplinary programs such as the Carolina Center for Genome Sciences, the Center for Environmental Health and Susceptibility, and the Bowles Center for Alcohol Studies. Rusyn points out that "this proposal brings together expertise across several biomedical and computational disciplines with a goal to develop and test computational strategies for integration of metabolomic data with other multi-dimensional data types for studies into the mechanisms of liver injury."


The ultimate premise of this research is to better understand the mechanisms of liver toxicity, to determine the phenotype-genotype links leading to susceptibility or resistance to disease, and to identify endpoints that can be used as biomarkers in animal and human studies. Importantly, the results of these studies will have important implications for the development of new research proposals. "Genetics takes center stage in biomedical research and medicine," concludes Threadgill, "and this project will show us how we can combine the knowledge of the genetic makeup of the individual with a potential outcome of exposure to environmental or lifestyle factors. Ultimately, such inquiry will provide an important foundation for individualized medicine."