Targeting and exploiting B cell functions for treatment in
To achieve these objectives Athero-B-Cell is organized in 6 Working Packages (WPs):
WP1: “Discovery of B cell specific therapeutic targets for CVD”
WP1 will take advantage of existing large-scale clinical studies available to Athero-B-Cell Partners from previous FP6 and FP7-funded collaborative work to perform B cell specific high-throughput proteomics and transcriptomics (including miRNA) in order to map B cell changes associated with CV outcomes and antibody status against lipoproteins. WP1 will also evaluate in humans and CVD patients a gene signature that distinguishes Bregs from pathogenic B cells that emerged from murine studies. Finally, WP1 will generate a list of candidate targets that relate to B cell behaviour in CVD.
WP2: “Target selection”
WP2 will bring together existing and new omics data generated in WP1 in a new repository and enlist state-of-the-art bioinformatic analyses. SME-based in silico platforms will aid the integration of multidimensional data from a large number of patients in terms of protein, mRNA and miRNA data for selection of the most relevant pathways forming a specific B cell signature associated with CVD outcomes and B cell effector functions. Bioinformatics will predict molecular outcomes and toxicity in silico. Verification of such a signature will be achieved using state-of-the-art B cell phenotyping methods, flow cytometry, ImageStream, and mass cytometry (CyTOF), to achieve unprecedented definition of the B cell subsets in CVD. Moreover WP2 will generate information on the atherosclerosis-related factors that condition B cell behaviour in CVD.
WP3: “Validation of novel targets for B cell responses with pro-atherogenic outcomes”
WP3 will employ the hits from the WP2 analysis to create new validation tools and use them to abate pro-atherogenic subsets and functions of B cells. Our validation strategy relies on the most advanced biotechnology tools in antisense therapy: the LNA platforms. The omics and biological data, once selected on the basis of bioinformatics filters, will be fed into the LNA pipeline to produce oligonucleotides for testing in the in vivo and in vitro models of CVD and novel mouse models.
WP4: “Validation of targets related to the enhancement of Bregs as a novel therapeutic strategy”
WP4 will focus on using the candidate targets emerging from WP1 and WP2 to enhance B regulatory cell function. LNA platforms and complex genetic modifications will be used in murine models to ascertain the best way to therapeutically exploit B regulatory cells for the abatement of CVD. The validation of the therapeutic targets will be performed in models of atherosclerosis with key readouts that include lesion development, antibody production against lipoproteins and B cell phenotypes.
WP5: “Management, review and assessment” and WP6: “Dissemination and training of Athero-B-Cell personnel”
WP5 and WP6 will focus on the maintenance of a management structure that allows for the smooth running of the project and on the dissemination of the knowledge created by Athero-B-Cell beyond the project partners to a wider community and potential users of the results.