DESCRIPTION (provided by applicant): The proposed research study will facilitate the improvement of the education and career goals of the principal investigator (PI). Moreover, the candidate will investigate the mechanisms that underlie impaired insulin secretion in type 2 diabetes mellitus (T2DM). The candidate has set up an important educative plan for the first two years (K99 phase) of the proposed study. This plan includes also courses. In addition, the candidate will be trained in scientific and professional research skills by his mentors and other experts. The candidate will perform experiments to investigate the molecular mechanisms underlying the functional role of intracellular calcium leak in the pathophysiology of T2DM and will suggest innovative, targeted therapeutic approaches for the treatment of such a disease. Upon conclusion of the mentored phase the candidate will have established a pool of data, knowledge and scientific skills that will enhance his credentials for successful transition to independence. During the K99 phase the candidate has planned to attend courses on biostatistics, grant writing/research funding, human subject protection, and responsible conduct of research. In addition, he has set up a specific training plan with his mentors and his advisors/collaborators that will provide him with scientific knowledge on ER stress/mitochondrial fitness, β-cell dynamics, ion channels. These aspects represent useful tools that he will be able to transfer to his own laboratory. Besides the new techniques that he will acquire, the proposed project requires knowledge in areas that he has only recently been associated with, such as mitochondrial pathophysiology and metabolic signaling. Therefore, he has included in his advisory board a number of scientists with outstanding careers in these particular fields that will provide guidance of the highest possible level. All his advisors and collaborators are top-notch academic scientists (see a complete list in Personnel, in the `Budget justification' document). The candidate will also present his work at several international meetings, in order to receive input by a broad scientific audience, thereby expanding his scientific network. This will promote his transition to an independent research position and provide him a robust scientific foundation from which to apply for independent R01-level funding. The application core questions are: (1) Which is the functional role of intracellular Ca2+ leak via RyR2 in pancreatic β-cells? (2) What i the mechanism underlying impaired glucose-stimulated insulin secretion in β-cells harboring leaky RyR2 channels? (3) How can the leak be prevented in human islets from T2DM donors or animal models of diabetes? (4) How the prevention of intracellular Ca2+ leak can impact the pathophysiology of T2DM? To address these questions the candidate has designed an experimental plan with two main branches. The first falls into the K99 phase and is based on ...