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Genetic Basis for Disease Susceptibility
International collaborations with many labs with mouse genetic models
The laboratory develops and uses state of the art genomic methods to identify genetic factors affecting disease susceptibility, and to translate these findings into new treatments.Computational mouse genetics: To reduce the cost and the time frame for genetic research, we developed a more efficient method for performing genetic analysis in mice. For this analysis, a property of interest is measured in ten or more inbred mouse strains; genetic factors are then computationally predicted by identifying genomic regions where the pattern of genetic variation correlates with the distribution of trait values among the inbred strains. This enables genetic analyses to be completed in far less time (days vs. years) and with far fewer personnel than conventional methods. In 2011, we developed a next generation version of this computational method, which analyzes whole genome sequence data for 20 inbred strains. This method has been used to analyze the genetic basis for 16 different biomedical traits. Clinical trials are currently underway that test the efficacy of 2 therapies that were generated by these genetic discoveries: a pilot study at Stanford to alleviate incisional pain after surgery and a multi-center NIH funded trial for preventing narcotic drug withdrawal in infants born to narcotic consuming mothers was begun in 2012.Metabolomic analysis: We are developing novel methods for analyzing changes in cellular metabolites caused by drug treatment or in disease. The metabolomic results are integrated with the genetic data to identify new disease mechanisms and to develop new diagnostics. Mice with human LIvers: This is a novel experimental in vivo platform that replaces mouse liver with functioning human liver tissue. The reconstituted liver was shown to be a mature and functioning human organ. It had zonal position-specific enzyme expression and bile duct function representative of mature human liver, and could generate a human-specific profile of drug metabolism. These features make this chimeric mouse the preferred experimental platform for in vivo analysis of drug metabolism or liver regeneration. The mice are maintained in a specialized barrier facility that was designed for housing these mice.The humanized mice are being used to: develop a novel platform for predicting human drug metabolism and human drug responses; for understanding stem cell development; and to develop a new method for liver transplantation that uses autologous cells without immunosuppression.