Host Susceptibility Group
Richard S. (Rick) Paules, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/ltp/esc/index.cfm)
Director, Molecular Genomics Core
Tel (919) 541-3710
The Host Susceptibility Group develops new approaches that can be used to understand genetic and epigenetic differences in susceptibility to toxicity and disease. The group quantifies what they refer to as "uncertainty factors" that are associated with environmental exposure and risk and identifies quantitative trait loci through genetic analysis (meiotic mapping, haplotype-phenotype segregation analysis, etc.).
Using reverse genetic approaches, the Host Susceptibility Group aims to perform functional validation and determine the relative contribution of the candidate genes to identify their allelic variants that modify individual response to chemical exposure and disease. By doing so, we aim to identify the key genes and pathways that modify or influence an individual response – and, thus, the variance observed within a population of individuals – to chemical exposures of presumed or known risk to humans.
Using the tools of toxicology, bioinformatics and comparative genetic analysis, the identification of human orthologs of causally related animal genes will aid the extrapolation between animal models and human toxicity and disease related to environmental, occupational, and/or medicinal exposures.
Major areas of research
- Population-level range of biological response to exposure related toxicity and disease using in vitro and in vivo based models for human populations
- Genetic and/or epigenetic basis for the mechanism/mode of action of disease causing exposures
- Identify the causally related mouse genic and/or intergenic sequences for functional validation and identification of human orthologs associated with highly conserved biological pathways to aid extrapolation between species
- Aging, survival, and spontaneous disease in 10 inbred strains
- Analysis of genetic differences in absorption, distribution, metabolism (ADME) to benzene exposure, a model human toxicant and a carcinogen to identify causally related genes and their allelic variants
- Analysis of uncertainty factors and susceptibility to benzene induced genotoxicity, and hematotoxicity phenotypes in a population based study (diversity outcross mice)
- Toxicokinetic models to benzene exposure in a population of inbred mouse strains
- Experimental short-term cancer bioassays (39 weeks or less) in F1 hybrid p53 haploinsufficient inbred strains to determine haplotype susceptibility to chemical and/or ionizing radiation induced disease
- Development of an experimental model genetic analysis of ephedra/caffeine or Bis(2-chloroethoxy)methane induced cardiotoxicity and chemical disposition in multiple inbred mouse strains
- Review and evaluation of in vitro endpoints for toxicity and genotoxicity