INFRAFRONTIER: mouse model resources for modelling human diseases.

Over the last decade, INFRAFRONTIER has positioned itself as a world-class Research Infrastructure for the generation, phenotyping, archiving, and distribution of mouse models in Europe. The INFRAFRONTIER network consists of 22 partners from 15 countries, and is continuously enhancing and broadening its portfolio of resources and services that are offered to the research community on a non-profit basis. By bringing together European rodent model expertise and providing valuable disease model services to the biomedical research community, INFRAFRONTIER strives to push the accessibility of cutting-edge human disease modelling technologies across the European research landscape. This article highlights the latest INFRAFRONTIER developments and informs the research community about its extensively utilised services, resources, and technical developments, specifically the intricacies of the INFRAFRONTIER database, use of Curated Disease Models, overview of the INFRAFRONTIER Cancer and Rare Disease resources, and information about its main state-of-the-art services.

INFRAFRONTIER: a European resource for studying the functional basis of human disease.

Ageing research and more generally the study of the functional basis of human diseases profit enormously from the large-scale approaches and resources in mouse functional genomics: systematic targeted mutation of the mouse genome, systemic phenotyping in mouse clinics, and the archiving and distribution of the mouse resources in public repositories. INFRAFRONTIER, the European research infrastructure for the development, systemic phenotyping, archiving and distribution of mammalian models, offers access to sustainable mouse resources for biomedical research. INFRAFRONTIER promotes the global sharing of high-quality resources and data and thus contributes to data reproducibility and animal welfare. INFRAFRONTIER puts great effort into international standardisation and quality control and into technology development to improve and expand experimental protocols, reduce the use of animals in research and increase the reproducibility of results. In concert with the research community and the International Mouse Phenotyping Consortium (IMPC), INFRAFRONTIER is currently developing new pilot platforms and services for the research on ageing and age-related diseases.

EMMA--mouse mutant resources for the international scientific community.

The laboratory mouse is the premier animal model for studying human disease and thousands of mutants have been identified or produced, most recently through gene-specific mutagenesis approaches. High throughput strategies by the International Knockout Mouse Consortium (IKMC) are producing mutants for all protein coding genes. Generating a knock-out line involves huge monetary and time costs so capture of both the data describing each mutant alongside archiving of the line for distribution to future researchers is critical. The European Mouse Mutant Archive (EMMA) is a leading international network infrastructure for archiving and worldwide provision of mouse mutant strains. It operates in collaboration with the other members of the Federation of International Mouse Resources (FIMRe), EMMA being the European component. Additionally EMMA is one of four repositories involved in the IKMC, and therefore the current figure of 1700 archived lines will rise markedly. The EMMA database gathers and curates extensive data on each line and presents it through a user-friendly website. A BioMart interface allows advanced searching including integrated querying with other resources e.g. Ensembl. Other resources are able to display EMMA data by accessing our Distributed Annotation System server. EMMA database access is publicly available at http://www.emmanet.org.

Regulatory context is a crucial part of gene function.

Information about the time and place of gene transcription, which until recently was only possible by extensive experimental analysis, can now be predicted through in silico analysis. Using the human RANTES/CCL5 promoter, we show that organizational features of promoters derived from promoter sequences contain information about the spatial and temporal 'functional context' of expression.

Computer modeling of promoter organization as a tool to study transcriptional coregulation.

Understanding how the regulation of gene networks is orchestrated is an important challenge for characterizing complex biological processes. Gene transcription is regulated in part by nuclear factors that recognize short DNA sequence motifs, called transcription factor binding sites, in most cases located upstream of the gene coding sequence in promoter and enhancer regions. Genes expressed in the same tissue under similar conditions often share a common organization of at least some of these regulatory binding elements. In this way the organization of promoter motifs represents a "footprint" of the transcriptional regulatory mechanisms at work in a specific biologic context and thus provides information about signal and tissue specific control of expression. Analysis of promoters for organizational features as demonstrated here provides a crucial link between the static nucleotide sequence of the genome and the dynamic aspects of gene regulation and expression.

Sesquiterpene lactones inhibit Yersinia invasin protein-induced IL-8 and MCP-1 production in epithelial cells.

Enteric Yersinia bacteria trigger transcription and secretion of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in epithelial cells. Both chemokines are controlled by NF-kappaB. The NF-kappaB-binding site in the IL-8 promoter preferentially binds Rel p65/p65 homodimers and p50/p65 heterodimers while the NF-kappaB-binding motifs of the MCP-1 promoter preferably bind p50/p65 heterodimers and p50/p50 homodimers. Sesquiterpene lactones inhibit the transcription factor NF-kappaB by alkylating the p65 subunit. In this study we investigated the inhibitory effects of sesquiterpene lactones and the NF-kappaB inhibitor SN50 on NF-kappaB p50 and p65 subunits in Yersinia-triggered IL-8 and MCP-1 production. The sesquiterpene lactones blocked Yersinia-triggered IL-8 and MCP-1 production in a dose-dependent manner. In contrast, SN50 inhibited IL-8 production at high concentrations whereas it diminished the amount of secreted MCP-1 significantly already at low concentrations. By means of electrophoretic mobility shift assays we demonstrate that sesquiterpene lactones inhibit Yersinia-triggered activation of NF-kappaB by inhibiting Rel p65, but not Rel p50. Our results also demonstrate that SN50 is useful for inhibition of nuclear translocation of the NF-kappaB p50 subunit but cannot be considered a general NF-kappaB inhibitor.