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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Resource-Related Research Projects (R24)
Project #
5R24OD011188-04
Application #
8695518
Study Section
Comparative Medicine Review Committee (RIRG)
Program Officer
Harding, John D
Project Start
2011-09-10
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
Singh, Neetu; Ramĩrez-Carvajal, Lisbeth; de Los Santos, Teresa et al. (2016) Inhibition of EHMT2 Induces a Robust Antiviral Response Against Foot-and-Mouth Disease and Vesicular Stomatitis Virus Infections in Bovine Cells. J Interferon Cytokine Res 36:37-47
Golding, Michael C; Snyder, Matthew; Williamson, Gayle L et al. (2015) Histone-lysine N-methyltransferase SETDB1 is required for development of the bovine blastocyst. Theriogenology 84:1411-22
Long, Charles R; Westhusin, Mark E; Golding, Michael C (2014) Reshaping the transcriptional frontier: epigenetics and somatic cell nuclear transfer. Mol Reprod Dev 81:183-93
Carnahan, Mindy N; Veazey, Kylee J; Muller, Daria et al. (2013) Identification of cell-specific patterns of reference gene stability in quantitative reverse-transcriptase polymerase chain reaction studies of embryonic, placental and neural stem models of prenatal ethanol exposure. Alcohol 47:109-20