Integral tissue regeneration is a major unmet medical need.The recent pivotal work of the coordinator provides a unique clinical situation of induced de novo generation of trachea and bronchus. Local immunoregulatory responses involving regulatory T (treg) cells responsive to IL-33 are important to promote tissue repair in animals. We aim at determining the optimal combination of immune cells and of specific molecules that promote tissue regeneration and repair from tissues with clinically occurring regeneration or in control trachea. Tissue cells and immune cells will be cocultured in invtiro sytems. We will verify in mice whether some combinations of molecules and specific cells such as Treg cells, can promote tissue repair in those mice.

Prostate cancer (PCa) is the most common cancer in male in Westernized countries and is a clinically heterogeneous disease with substantial variability in progression. Emerging studies support a crucial role of metabolic plasticity of prostatic tumor cells with fatty acids and sterols being demonstrated to represent hallmarks of aggressiveness in PCa. In this context, targeting prostate cancer cell metabolism and more specifically lipid metabolism show great promise for developing alternative adjunct therapies to be used in combination with chemotherapy and androgen deprivation therapy. Moreover, alterations in the epigenome, due to modulation of histone and DNA modification enzymes that results from metabolic reprogramming driven by oncogenes and expression of metabolism-associated genes have been associated not only with neoplastic transformation, but also with cancer aggressive biology. The overall objective of our research and training network PROSTAMET, is to enhance the knowledge and understanding of metabolic changes that occur at the primary as well as the metastatic sites of prostate cancer in order to identify new markers of aggressiveness and/or new therapeutic targets related to lipid metabolism. Study of the lipid metabolism of tumor cells and the impact of cellular components of the microenvironment together with the design and assay of new pharmacological compounds will be used as a platform to develop an interdisciplinary training program on tumor aggressiveness, cell metabolism, structural biology, and the development of novel metabolism modulators. The overall goal of our project is to assemble a consortium of world-renown experts in prostate cancer, lipid metabolism and development/screening of novel anti-tumor drugs in order to train the new generation of young researchers involved in the field of cancer. Our consortium will combine research-based training in the field of metabolism, epigenetics and prostate cancer research and development together with training in relevant transferable skills such as IP management, communication, personal and career development and entrepreneurship into an Initial Training Network (ITN) proposal. To achieve this goal, we have assembled a core consortium of relevant experts with international repute. The MRSEI grant will allow us enlarging and consolidating this core consortium with additional complementary partners from the public and private sectors. Combining the skills in cancer research and analytics with industrial quality management and transferable skills will increase the chances of our early stage researchers of productive and successful careers in their chosen sectors.

Plasma cells and the antibodies they secrete are essential for long-term protective immune responses and tissue homeostasis. However, they can also contribute to the pathology of numerous inflammatory and autoimmune conditions. Despite their relevance in health and disease, the mechanisms underlying antibody production and secretion are still poorly understood. This is an essential question as a better characterization of the involved molecular actors may pave the way to improved antibody production, and to the development of new therapies for antibody-driven diseases. Preliminary data obtained in our laboratory showed that the Sec22b SNARE is essential for antibody secretion but also for plasma cell maturation. Using a conditional mouse model we observed in absence of Sec22b in the B cell lineage an almost complete lack of circulating antibodies and a dramatic decrease in the number of plasma cells in the spleen and the bone marrow. We now plan to use this model to address how Sec22b affects plasma cell fitness and antibody secretion. In parallel we will determine the impact of such defects on the normal and pathological humoral immune response and on tissue homeostasis, in particular in the BM. Collectively, this project should bring new lights on the molecular mechanisms underlying antibody secretion by plasma cells, a key process with huge relevance both at the therapeutic and at the industrial levels but largely overlooked so far. Moreover, our model will allow us to study with great details the impact of plasma cells and antibodies on homeostasis and inflammation at the tissue and organism level.