Gene Array Technology Center for Alcohol Research (The R-GAP)

描述（由申请人提供）：此竞争性修订申请是对NOT-OD-09-058的回应：NIH宣布竞争性修订申请的恢复法案资金的可用性，并用于补充我们原始的R24，啮齿动物基因阵列计划（R-GAP）的资金。在我们目前的R24中，我们正在收集大型LXS重组近交系小鼠的全脑转录组数据，并将这些数据发布在我们的公共网站（http://phenogen.uchsc.edu）上。在本补充中，我们将重点在涉及酒精中毒负面影响的4个组织（心脏、肝脏、肠道和棕色脂肪）的重组近交系大鼠的大型面板上建立基因表达和基因型数据库。转录组数据将在Affymetrix大鼠外显子1.0 ST阵列上收集，以便进行转录和外显子水平的分析以及剪接变异的分析。我们将使用100K SNP阵列收集整个大鼠品系的广泛基因型数据。生成的数据可用于鉴定与酒精中毒相关的内表型易感性的候选基因，使用鉴定转录本的分析策略，这些转录本不仅与内表型相关，而且在控制内表型（pQTL）的基因组的同一区域（eOTL）控制其转录。这些有价值的新数据集和我们的分析工具将进一步催化eOTL定位，以及目前使用大鼠行为和酒精诱导器官病理模型获得的酒精相关行为的qtl定位。我们在我们的具体目标中包括使用最新技术开发的遗传作图，转录组学和细胞分离。这些技术进步将有助于确保我们的数据集的长期相关性。利用全基因组转录组学和基因组学，我们可以开始识别系统而不是单个基因作为治疗的目标。通过评估多种组织和细胞类型的基因表达，我们还可以帮助解开细胞分化的许多谜团，以及威胁生命的疾病发生过程中组织之间的相互作用。在所有技术和环境因素保持不变的情况下，目前或预计没有如此大量的外显子表达数据和基因型信息在大鼠多个组织中的组合。当然，我们数据的最终用途是深入了解并产生可测试的假设，以解释人类与酒精相关的病理。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.