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宣布恢复法案资金可用于竞争性修订申请，并用于补充我们最初的R24，啮齿动物基因阵列计划（R-GAP）。在我们目前的R24中，我们正在收集大型LXS重组近交系小鼠组的全脑转录组数据，并在我们的公共网站（http：//www.example.com）上提供这些数据。phenogen.uchsc.edu对于这个补充，我们将专注于创建基因表达和基因型数据库的一个大面板的重组近交系大鼠品系跨4个组织，参与酒精中毒的负面影响（心脏，肝脏，肠道和棕色脂肪）。转录组数据将收集在Affytek Rat Exon 1.0 ST阵列上，以便分析转录本和外显子水平以及剪接变异分析。我们将使用100 K SNP阵列收集整个大鼠品系的广泛基因型数据。该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，使用鉴定不仅与内表型相关，而且其转录由控制内表型（pQTL）的基因组的相同区域（eOTL）控制的转录物的分析策略。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。我们的具体目标包括使用最新的遗传图谱、转录组学和细胞分离技术。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靶点。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奥秘以及危及生命的疾病发生中组织之间的相互作用。在所有技术和环境方面保持不变的情况下，大鼠多个组织中没有如此大量的外显子表达数据和基因型信息的当前或预计组合。当然，我们的数据的最终用途是深入了解并产生可验证的假设，以解释人类与酒精相关的病理。 公共卫生相关性：该数据库的可用性与我们的其他数据相结合，有可能在医学研究的几个领域产生重大影响，包括药物发现，个性化医疗以及组织分化和疾病所涉及的生物学。整合遗传/功能基因组/表型方法来鉴定易患疾病、促进疾病进展甚至确定对药物的反应的多基因途径在许多疾病领域具有深远的影响。

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.