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Periodic Report Summary 2 - APPI (Antagonists of protein-protein interactions)

The first challenge in APPI has been to find the suitable DNA-sample collections. The Genetics of Kidneys in Diabetes (GoKinD) Study supported the project with a DNA collection and clinical information from more than 3 000 adults with long-term Type 1 diabetes, with or without kidney disease, along with their parents. Another DNA collection with clinical information from 395 adults was provided by The Clinic of Gastroenterology, Hepatology and Infectious Diseases of Otto von Guericke-University Magdeburg, Germany. After collecting the required sample collections, a further challenge was the management of the enormous amount of generated data and their statistical analysis. For this, the data analysis software, SNP & Variation Suite (SVS) from Golden Helix, has been used which is a powerful tool for managing, analysing, and visualising large-scale, complex genomic data.

In the GoKinD study, distinct single-nucleotide polymorphisms (SNPs) were identified in two CXCL chemokine genes, which are associated with measures of kidney function in Type-1-Diabetes (T1D) patients. These polymorphisms lead to a disparate regulation of CXCL chemokine genes in kidney cells. Following functional characterisation of these polymorphisms, relevant cell-based assays have been designed and utilized for screening of different compound libraries. Two secondary metabolites from myxobacteria were found which inhibit the expression of CXCL chemokine genes. Patent claims have been filed for the medical use of both metabolites.

A database have been developed that collects accumulating information on altered structural and functional organisation of protein-protein interactions in inflammatory diseases. Peptide-mapping experiments have been conducted to discover the important protein motifs that are involved in pro-inflammatory protein-protein interactions. Three protein motifs have been discovered in NF-kB p65 protein, a crucial regulator of inflammatory genes, which hint at promising targets for new inhibitors of inflammation.

In the gastric cancer study, similar approaches were used to analyse the effect of the associated gene polymorphisms on the level of protein expression and the downstream signalling pathways in gastric cells. The Gram-negative bacterium Helicobacter pylori colonises gastric epithelial cells and increases the risk for gastric disease, including gastric cancer. HP is able to establish a dynamic equilibrium in human stomach which is different for each colonized individual based on host and bacterial characteristics. The expression of distinct CXCL chemokine genes contributes to this equilibrium by attraction of immune cells. The gastric cancer study has shown that the level of CXCL genes expression in gastric epithelial cells strongly also depends on the specific severity of Helicobacter pylori in individuals. This leads to differential activation of signalling pathways, their downstream transcription factors, and CXCL genes expression. Although these in vitro studies do not necessarily predict disease outcomes, it is tempting to speculate that the extent of host CXCL gene response is based on individual genetic predispositions and the specific rate of infection. The data is very promising for the design of new therapeutic strategies.

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