Functional Validation of Candidate Genes Deriving from Convergent Analysis of Gene Expression Profiling in Nicotine Self-Administering Animals and Genome Wide Association Studies in Smokers

• Applicant: Professor Dr. Rainer Spanagel
• Subject Area: Biological Psychiatry
• Term: from 2009 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 147436574

Background: Consistent evidence for the heritability of smoking behaviours has led to genetic studies designed to elucidate the specific genetic factors involved in nicotine addiction. The most advanced scientific approaches to address this question include genome-wide association studies (GWAS) in smokers and gene expression profiling studies in animal models of nicotine self-administration. Convergent translational genomics approaches allow integrating genetic findings from animal models with a GWAS approach in humans and have proven to be very successful in generating priority candidate gene lists. However, the demonstration of a causal relationship of a candidate gene with a given pathological phenotype remains the biggest challenge in the emerging field of genetic research. Goals: In this proposal we want to integrate our previous genetic findings from massive gene expression profiling in animals that underwent chronic nicotine self-administration with the human genetic data sets deriving from the German Priority Programme on Nicotine Research Project (Project P2 (Dahmen), P3 (Winterer), P9 (Brenner), P10 (Winterer), and P11 (Steinlein)). By applying a convergent translational genomics approach data integration will be performed and a priority candidate gene list for the entire Research Project will be generated. From this priority gene list for nicotine addiction we will functionally validate the top hits in an animal model of nicotine self-administration and relapse by means of recombinant adeno-associated virus (rAAV)-mediated gene transfer into brain sites of the reward system (especially into the nucleus accumbens shell). The advent of AAV vectors carrying cDNA for, or short hairpin RNA against, specific genes allows now for the first time the rapid bidirectional manipulation of gene function in nicotine self-administering animals. Both applicants have proven expertise in animal models of addictive behaviour and rAAV-mediated gene transfer technology, respectively.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1226: Nicotine: Molecular and Physiological Effects in the Central Nervous System (CNS)
• Ehemaliger Antragsteller: Professor Dr. Matthias Klugmann