APPI · ANTAGONISTS OF PROTEIN-PROTEIN INTERACTIONS

Periodic Report Summary 1 - APPI (Antagonists of protein-protein interactions)

The main goal of this project is to bring together the following three distinct research fields: regulation of cytokine and cytokine genes, translational genomics and chemical biology. The initial phase of this research project focused on the most common genetic variations, single nucleotide polymorphisms (SNPs) which occur approximately once every 100 to 300 bases. According to the research objectives, a new data base was established based on data obtained from dbSNP which is incorporated into NCBI's Entrez system and can be queried using the same approach as the other Entrez databases such as PubMed and GenBank. The new database contains two intersections containing SNPs in cytokine and cytokine receptor genes with possible effects on 1) gene expression level and 2) protein structure. This step involved biostatistics, and data visualisation techniques to complex biomedical and clinical research in inflammatory and infectious diseases as well as data management systems for known protein-protein interaction patterns to simulate complex biological systems. Of 1600 evaluated SNPs, 122 SNPs were selected to be genotyped in four different assays in two different DNA repositories. First repository contains DNA samples of more than 3 000 adults with long-term Type 1 diabetes, with or without kidney disease. Second repository contains DNA samples of 395 adults including 116 patients with gastric cancer and 142 high risk gastritis as well as 94 healthy controls. In the first study, 10 SNPs showed significant association with impaired kidney function (95 % confidence interval > 2.0). 34 SNPs showed significant association with gastric cancer (95 % confidence interval > 2.0) and 38 SNPs with higher risk of gastritis (95 % confidence interval > 2.0). However, joint evaluation of several cytokine variants suggested an increased risk of gastric cancer and gastritis of among individuals carrying 15 SNPs in cytokine and cytokine receptor genes. Based on these results, relevant cell-based reporter assays were designed monitoring the effects of the identified SNPs on gene expression level or on protein-protein interactions. Progress report and results The initial phase of this research project focused on the Helicobacter pylori induced gastritis and gastric cancer as well as the chronic kidney disease. Cytokine and cytokine receptors play a fundamental role in the development of both diseases. Cytokine gene expression is tightly regulated, and aberrant expression from environmental and genetic polymorphism has been implicated in a range of diseases, susceptibility to infections, and responses to treatment. Thus, this work first concentrated on the functionality of cytokine and cytokine receptor gene polymorphisms. The most common variations are single nucleotide polymorphisms (SNPs), which occur approximately once every 100 to 300 bases. The dbSNP has been designed to support submissions and research into a broad range of biological problems. These include physical mapping, functional analysis, pharmacogenomics, association studies, and evolutionary studies. Because dbSNP was developed to complement GenBank, it may contain nucleotide sequences from any organism. According to the research objectives, a new data base was established based on data obtained from dbSNP which is incorporated into NCBI's Entrez system and can be queried using the same approach as the other Entrez databases such as PubMed and GenBank. The new database contains two intersections containing SNPs in cytokine and cytokine receptor genes with possible effects on 1) the level gene expression and 2) the protein structure. In total, 1 600 SNPs were evaluated and imported to the database. Depending on the scope of the research project, categories of single nucleotide polymorphisms (SNPs) genotyping experiments range from low to medium to high throughput, with each approach differing widely in cost, platform, and efficiency.

Data: CORDIS, © European Union