This competitive revision application is in response to NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications and is for funds to supplement our original R24, The Rodent Gene Array Program (R-GAP). In our current R24, we are gathering whole brain transcriptome data on the large LXS recombinant inbred panel of mice and making this data available on our public website (http://phenogen.uchsc.edu). For this supplement we will focus on the creation of gene expression and genotype databases on a large panel of recombinant inbred rat strains across 4 tissues that are involved in the negative effects of alcoholism (heart, liver, gut, and brown fat). Transcriptome data will be gathered on the Affymetrix Rat Exon 1.0 ST array to allow for analysis on the transcript and exon level and the analysis of splice variation. We will be collecting extensive genotype data for the entire panel of rat strains using 100K SNP arrays. This generated data can be used to identify candidate genes for predisposition to endophenotypes related to alcoholism using an analytical strategy of identify transcripts that are not only correlated with the endophenotype, but also have their transcription controlled from the same area (eOTL) of the genome that controls the endophenotype (pQTL). These valuable new datasets and our analysis tools will further catalyze eOTL mapping, as well as mapping of QTLs for alcohol-related behaviors currently being acquired using the rat models of behavior and alcohol induced organ pathologies. We have included in our specific aims use of the latest technology developed for genetic mapping, transcriptomics, and cell separation. These technologic advances will help to assure the long lasting relevance of our data sets. Utilizing genome-wide transcriptomics and genomics, we can start identifying systems rather than individual genes as targets for therapeutics. With assessment of gene expression across multiple tissues and cell types, we can also help to unravel the many mysteries of cell differentiation as well as interactions between tissues in the genesis of life threatening disease. There are no current, or projected, combinations of such large amounts of exon expression data and genotype information across multiple tissues in the rat where all technical and environmental aspects are held constant. The ultimate use of our data is, of course, to get insight into and generate testable hypotheses to explain alcohol related pathologies in humans.
The availability of this database in concert with our other data has the potential to make a significant impact in several areas of medical research including medication discovery, personalized medicine, and the biology involved in tissue differentiation and disease. The integration of genetic/functional genomic/phenomic approaches to identify the polygenic pathways which predispose disease, contribute to disease progression, and even determine the response to medication have far reaching implications in many disease areas.
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| Rudra, Pratyaydipta; Shi, Wen J; Russell, Pamela et al. (2018) Predictive modeling of miRNA-mediated predisposition to alcohol-related phenotypes in mouse. BMC Genomics 19:639 |
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| Saba, Laura; Hoffman, Paula; Tabakoff, Boris (2017) Using Baseline Transcriptional Connectomes in Rat to Identify Genetic Pathways Associated with Predisposition to Complex Traits. Methods Mol Biol 1488:299-317 |
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| Abdelmagid, Nada; Bereczky-Veress, Biborka; Atanur, Santosh et al. (2016) Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis. PLoS One 11:e0155832 |
| Harrall, Kylie K; Kechris, Katerina J; Tabakoff, Boris et al. (2016) Uncovering the liver's role in immunity through RNA co-expression networks. Mamm Genome 27:469-84 |
| Vanderlinden, Lauren A; Saba, Laura M; Bennett, Beth et al. (2015) Influence of sex on genetic regulation of ""drinking in the dark"" alcohol consumption. Mamm Genome 26:43-56 |
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