Proposal Title FRG KO humanized-liver rat
Category Human Health and Development
Abstract Greater than 88% of potential human therapeutics fail during clinical trials with no more than 1% of drugs in the pipeline reaching the marketplace. One major reason for drug failures is human-specific liver toxicity, which cannot always be predicted using traditional animal models. While the use of humanized-liver mice has transformed screening for human-specific toxicity, toxicity studies often require collection of multiple blood samples at different time points, which is extremely challenging in mice. The laboratory rat has been the preferred laboratory animal in industry because their greater blood volume allows for collection of multiple samples from the same rat. Thus, the creation of rat models with humanized livers would provide valuable resources to assess the physiological effects of drug metabolites in the whole animal as well as human-specific drug induced liver injury (DILI). One approach to humanize an animal is to replace entire cell-populations or organs of the host animal with those from a human. This must be done in an immunodeficient animal so that it cannot reject the human cells/tissue. Last year (2015-2016), funded by the Kentucky SBIR/STTR matching funds program (KSTC 184-512-15-219), we have created a Severe Combined Immuno-Deficiency (SCID) rat in which, immune system related genes Rag2 and Il2rg have been functionally disrupted. If awarded this matching grant for another year, we will ablate the endogenous hepatocytes of the SCID rat, and transplant human hepatocytes, to create the first-ever humanized-liver rat for human liver-specific and whole animal toxicity testing. In this proposal, 1) we will assess the capability of our SCID rats to accept and accommodate human xenograft transplantations, 2) we will assess different methods and hepatocytes to achieve at least 50% humanization of the liver in our SCID rats, 3) we will characterize the functionality of humanized-liver and demonstrate human-specific metabolic activities.
Amount Awarded $400,000
Keywords SCID rat, humanized rat, humanized liver, immunodeficient, DILI, hepatotoxicity, humanization, CYP induction, P450,
Point of Contact Eric Ostertag
[email protected]
Hera Testing Laboratories Inc
Location Lexginton
fayette County