The overall goal of this research proposal is to develop inducible, tissue-specific expression of transgenes to produce large animal models of human disease. There is a critical need to expand functional genomics to non-rodent models and the limited application of technologies, which have been so successful in rodent models, in large animals requires an alternate approach. The specific objective of this proposal is to develop effective tissue-specific, inducible expression of transgenes in vitro, then utilize recombinant lentiviral vectors to deliver these transgenes into porcine zygotes and evaluate the expression platforms in resulting offspring. The target gene for these experiments will be Stearoyl-CoA desaturase (SCD-1) and will serve as an effective and efficient model for examining local control of gene expression in vivo. Although any number of genes could be utilized, SCD-1 has been documented to have an important role in lipid biosynthesis and its tissue specific expression is important in maintaining homeostasis. Therefore, the resulting animals will not only demonstrate the effectiveness of the technology platform, but also serve as a useful model of failed lipid metabolism in a tissue-specific manner. Development of this technology, and utilization of this gene target is central to investigation of diseases such as obesity, insulin resistance and associated metabolic disorders, as well as, muscle and hepatic steatosis. Most importantly, successful completion of this project will result in technological advancements useful to produce a wide variety of biomedical models in numerous large animal species, potentially targeting a huge range of genes, thus benefiting many of the NIH Institutes and Centers.
Developing therapies to treat human disease requires extensive investigation of gene function in relevant animal models. When naturally occurring animal models do not exist, production of genetically engineered animals that mimic human disease is necessary. Our project will develop the technology to reliably induce tissue-specific expression of genes so that disease states can be mimicked in non-rodent species.
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