Background: EU countries face large health challenges to combat chronic diseases. Recently, systems medicine has emerged as a promising discipline to accelerate the translation of basic research into applications for improved diagnostics and personalized treatment. Its power arises from the integration of laboratory and computational approaches crossing research disciplines and sectors to solve clinical questions. COSMIC delivers the next generation of leading, entrepreneurial, and innovative systems medicine professionals having expertise, skills, and experience to successfully combat complex human disorders. These professional will find excellent career opportunities. COSMIC focuses on B-cell neoplasia and rheumatoid arthritis, prototypical diseases originating from abnormal functioning of immune cells, often resulting in similar antigen specificities. COSMIC enables Early Stage Researchers to play a leading role in this exciting field. Approach: COSMIC develops and integrate experimental and computational approaches and establish a unique cross-fertilization between oncology and auto-immunity. In addition to transferable skills, the training program focuses on establishing a double expertise in laboratory and computational to address clinical questions. It involves a wide-range of stakeholders: (pre)clinical departments, companies, patient groups, students, and the general public. COSMIC will establish a link with the leading European EASyM and ISBE initiatives, and aims to harmonize systems medicine training throughout Europe by connecting to other EU (Marie Curie systems medicine) training initiatives. Impact: COSMIC (i) significantly improves ESR career perspectives (ii) leads to new public-private collaborations increasing competitiveness for companies; (iii) contributes to future oncology and immunology medical care; (iv) contributes to the EU systems medicine best practices.

The Phosphoinositide 3-kinase (PI3K) pathway is at the core of multiple fundamental biological processes controlling metabolism, protein synthesis, cell growth, survival, and migration. This inevitably leads to the involvement of the PI3K signalling pathway in a number of different diseases, ranging from inflammation and diabetes to cancer, with PI3K pathway alterations present in almost 80% of human cancers. Therefore, PI3Ks have emerged as important targets for drug discovery and, during 2014, the first PI3K inhibitor was approved by FDA in the US for the treatment of a lymphocytic leukaemia. Nonetheless, our understanding of PI3K-mediated signalling is still poor and only a fraction of the potential therapeutic applications have been addressed so far, leaving a large amount of translational work unexplored. Europe features a set of top quality research institutions and pharmaceutical companies focused on PI3K studies but their activities have been so far scattered. This proposal fills this gap by providing a multidisciplinary network (biochemistry, mouse studies, disease models, drug development, software development) and an unprecedented training opportunity from the bench to the bedside (from pre-clinical discoveries to clinical trials), through cutting edge molecular biology, drug discovery and clinical trial organization. The proposal is aimed at training young investigators in deep understanding of the different PI3K isoforms in distinct tissues and to translate this knowledge into a new generation of PI3K inhibitors, treatment modalities and into identify new uses for existing PI3K inhibitors.

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One of the ways in which the immune system fights infections is by using B lymphocytes, white blood cells that make antibodies. These antibodies attack and remove the many foreign agents such as bacterial toxins that the body encounters. Since there are literally millions of different possible invading proteins that the immune system may have to deal with, B cells of higher species, including mice and man, have evolved a way of making millions of different antibodies. They are made by cutting and pasting together one each of three different kinds of gene segments: V, D and J, to make an immunoglobulin protein. There are several D and J genes and 200 V genes, thus many different combinations can be made and this process, called V(D)J recombination, together with other associated processes, ensures that the immune system produces a sufficient diversity of antibodies to fight infection. The enormous DNA locus that contains all of these genes must be kept shut down in most cells since the DNA cutting and pasting involved can be very damaging to cells because the gene segments can paste to DNA sequences on other chromosomes by mistake, leading to chromosomal translocations that can cause cancerous B cell lymphomas. Equally it must be opened up efficiently in B cells to allow the cutting and pasting enzymes access to all the genes to generate a diverse repertoire. If some of the genes are not opened up, this can lead to immunodeficiency since there is a limited choice of gene segments to make antibodies. We have discovered that just before V(D)J recombination, RNA transcripts are made through the large antibody DNA locus. They are highly unusual because they do not make protein and they are made from the opposite strand of DNA to the genes themselves. It has recently been shown by genome mapping studies that this type of 'opposite strand' or 'antisense' transcription occurs throughout the genome, but its function is unknown. The key aim of our work is to discover the function of this non-coding RNA transcription in V(D)J recombination. This will also contribute to our understanding to its role in the rest of the genome. The only way to do this unambiguously is to stop this transcription in mouse B cells to determine what effect it has on V(D)J recombination and production of antibodies, and also how it achieves such effects. We plan to do this in a mouse model, since all the processes associated with making antibodies are very similar in mouse and human B cells. We have developed a technique to visualise by fluorescent microscopy what happens at each DNA locus in individual B cells. Overall this work will tell us what function this large-scale non-coding RNA transcription has in V(D)J recombination. This work will (i) help us to understand how B cells make antibodies and (ii) may also identify molecules or processes that are involved in human disease, such as immunodeficiency and lymphomas. Further studies would then be possible to develop diagnostic tests and treatments for these diseases. This research will contribute to the BBSRC's aims of understanding fundamental mechanisms of gene regulation and normal healthy development, and of improving quality of life.