Organ transplantation increases survival and quality of life of patients with end stage chronic diseases. However, despite advances in surgical techniques and new immunosuppressive drugs, a significant number of patients still presents with acute rejection, which is a risk factor for graft loss. Graft loss leads to difficulty in being retransplanted due to patient sensitization with development of specific antibodies against the donor, which is contraindicated for holding a new transplant. Therefore, more specific and new strategies to increase acceptance of the graft needs to be studied. B cells have a critical role in the rejection process, either through presentation of the antigen or by the production of alloantibodies, but may also be involved in graft tolerance process where the regulatory B cells, Bregs, might play a role. Recently, it has been found that cellular metabolism is critical to the survival and activation of immune cells, such as metabolic sensors and orchestrators of these functions. However, very little is known about the role of metabolic pathways and metabolic sensors such as AMPK and mTOR in the activation process and function of B lymphocytes, and more about the impact of these pathways in organ transplantation. This project aims to better understand the influence of metabolic pathways of B cells and their sensors in an experimental model of transplant skin, as these might interfere in allograft. Thus, we hypothesize that the metabolic pathways, AMPK and mTOR, are critical in the activation of B lymphocytes during the process of allograft rejection. We will use cell biology and molecular tools to dissect the involvement of metabolic pathways in the activation of B cells, and compare the metabolism of different types of lymphocytes B. We also evaluate the participation of mTOR molecules and AMPK activation and differentiation of B lymphocytes in a skin graft model. We believe that this project will contribute to the understanding of cellular metabolism role in the immune cell activation and in the future may contribute to the development of new targets and therapeutic strategies for the treatment of transplant rejection and other inflammatory processes.
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