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Gene Array Cores

Colorado Gene Array Core

Boris Tabakoff, Ph.D.
University of Colorado Health Sciences Center Denver
Department of Pharmacology

1U01 AA016663     30 September 2006 - 31 August 2011

The Colorado Gene Array Core will focus on the creation of databases that can be used for developing expression QTL (eQTL) maps for mouse and rat brain. We are currently expanding the database of brain gene expression profiles for males and females of the BxD Rl mouse strains. The proposed studies will generate a similar database of gene expression profiles from brains of 31 Rl strains of BxH/HxB rats and the progenitor strains (males and females separately), and microsatellite and SNP genotyping of the rat strains will be performed in collaboration with Dr. Rob Williams, University of Tennessee. This information will allow for eQTL mapping for rat brain gene expression as well as mapping of QTLs for alcohol drinking in the rat strains. When combined with QTL analysis of complex traits, the generation of eQTLs facilitates the identification of candidate genes for these traits, and the Core will use this procedure and the generated data to identify candidate genes that contribute to anxiety and other alcohol related behaviors in the rats. The availability of brain gene expression data and eQTL mapping of the mouse and rat brain transcriptome will produce a novel and unique resource for use by alcoholism investigators. The Core will also perform gene expression analysis and quantitative RT-PCR for collaborating INIA investigators, and provide access to methodology for normalization, statistical analysis and eQTL searches of the generated data.

Indiana Gene Array Core 

Howard Edenberg, Ph.D.
Indiana University Purdue University at Indianapolis
School of Medicine

1U01 AA016660     30 September 2006 - 31 August 2011

The overall aim of the Indiana Gene Array Core is to collaborate with INIA investigators to understand the differences in gene expression in the extended amygdala that are involved in the development of excessive drinking. Our hypothesis is that both innate differences in gene expression and differences in response to alcohol and to paradigms involving exposure to alcohol or its withdrawal (gene-environment interactions) contribute to the development of excessive alcohol drinking. The Indiana Gene Array Core will focus on the use of Affymetrix microarrays to measure gene expression in selected regions of rat brains and in Drosophila mutants after various treatments; primary collaborators will be McBride (U01), Ryabinin (U01) and Davis (U01). These studies build upon our work during the initial grant period; carrying out the follow-up studies in the same laboratory (with many of the same technical personnel) will reduce technical variations and allow more powerful metaanalyses. We will work with investigators on experimental design, extract and purify RNA from rat brain tissues provided by the collaborating investigators, carry out all of the quality control and biochemistry involved in GeneChip experiments, extract the data and assist with analyses and bioinformatics. This core will be housed in the Center for Medical Genomics, directed by the PI, which has all of the necessary equipment and carries out a high volume of Affymetrix GeneChip experiments with a focus on quality control. We will extend our services to include quantitative RT-PCR confirmation of key findings from the microarrays that we process, and will offer such services to other members of INIA. We will also provide members of INIA analyses of cis-acting elements that contribute to the differences in gene expression detected in the microarray experiments; we have developed model-based techniques that do not require prior knowledge of binding sites. This Core will provide high quality data in an efficient and economical way. We already have strong relatioinships with the users, which will benefit the overall project.

RNAi Core

Mike Zawada, Ph.D.
University of Colorado Health Sciences Center Denver
Division of Clinical Pharmacology & Toxicology

1U01 AA016654     30 September 2006 - 31 August 2011

The original five-year INIA West has identified a large number of candidate genes that are differentially expressed in the brains of mice selectively bred for either high- or low-preference for alcohol. Additional conserved genes were identified in screens for alcohol tolerance in Drosophila. Manipulating the expression of these genes has naturally become a critical component of studies designed to further define their role in the development of alcohol preference or tolerance. The RNA Interference Core (RNAi Core) will provide a means for systematic modification of the target genes' expression in selected and precisely-defined brain areas. Two technological platforms for in vivo RNA interference will be employed: (1) small interfering RNA (siRNA) delivered by a direct injection or infusion into the CNS and (2) short hairpin RNA (shRNA) delivered via a lentiviral vector-based transduction. Initially, these methods will be standardized using transcripts identified in HAP and LAP mice as contributing to alcohol preference drinking behavior, and the functional consequences of the RNAi treatment will be assessed in these mice. The successful implementation of the methodology will provide an important resource for all INIA investigators, including those working with rat models. At the time of this submission, laboratories from California, Colorado, Indiana, Oregon and Texas are already collaborating in both Binge and Dependence Domains. The core will also perform RNAi treatments for INIA investigators, who will develop need for RNAi services with the emergence of additional target genes. Proposed projects will be evaluated for integration with INIA West goals by a Project Evaluation Committee composed of members of the INIA Steering Committee and an independent consultant. The core will capitalize on our ongoing collaboration with Dharmacon Corporation, a leader in the field of siRNA development. Dharmacon will provide many of the necessary reagents and work with us on improving the efficiency of gene silencing in the CNS. The core's goals will be accomplished by successful completion of the following aims: Aim 1. Perform high throughput in vitro screening of the RNAi sequences targeting the genes of interest. Aim 2. Silence expression of selected genes in vivo employing RNAi within precise neuroanatomical targets. Aim 3. Examine behavioral and transcriptional effects of gene silencing. The creation of the RNAi core is a logical extension of the work already completed by the INIA. The core will allow for systematic and high throughput manipulation of genes in the mammalian CNS, facilitating functional studies of these genes in alcohol preference.

Texas Gene Array Core

Robert Adron Harris, Ph.D.
University of Texas at Austin
Waggoner Center for Alcohol and Addiction Research

2U01 AA013518     27 September 2001 - 31 August 2011

The overall objective of this INIA core is to continue to provide robust microarray analysis and informatics capabilities to INIA researchers. During the previous grant period, the INIA Microarray Core at UT Austin enabled the generation of large amounts of microarray data from INIA labs. In the next period, although we plan to generate microarray data, the emphasis of the Core will extend to carrying out novel analyses of consolidated datasets. At the same time we will enhance our microarray capabilities by enabling novel types of microarray profiling experiments such as microRNA (miRNA) profiling and chromatin immunoprecipitation (ChlP-chip) data analysis. The activities of this proposed INIA Core will include updating of our relational microarray database, the Longhorn Array Database (LAD), to accommodate these novel kinds of experimental platforms and datasets, and most importantly, developing completely new analysis capabilities that are not possible with the web browser model that is used by LAD. miRNAs provide a novel mechanism for changing function by changing the levels of brain proteins and we will enable INIA investigators to carry out pioneering neurobiological studies in this area. miRNAs have been shown to be important in post-transcriptionally regulating gene expression in cancer and miRNA profiling is likely to be valuable for understanding INIA models of excessive alcohol consumption. This core will give INIA researchers free access to the analyses tools for DNA microarray data that we have developed and are developing by making these accessible from a web browser. For example, generalized singular value decomposition (GSVD) and pseudoinverse projection, allow construction of predictive models from DNA microarray data. This website will enable researchers without in-depth expertise in mathematics and computer programming to concentrate on the scientific questions they set out to answer by analyzing cDNA, miRNA and oligonucleotide microarray data.


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