Evaluation of signals mediating beta-cell regeneration

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 DESCRIPTION (provided by applicant): Type 1 diabetes is a syndrome defined by high blood glucose levels caused by reduction in number of insulin producing cells, thus a cure for diabetes should entail replacement of ß-cells. There is a genetic predisposition for autoimmune susceptibility regarding macrophage phenotype in NOD mice and human T1D-patients, which contributes to persistence of inflammation, and ß-cell destruction. Here, we provide evidence that macrophages are important elements of pancreatic regeneration in general, and ß-cell generation in particular. Furthermore, we demonstrate that macrophages isolated from the NOD strain have an inherent inability to induce ß-cell generation. In this proposal, we will test the central hypothesis that Type1 diabetes is the combined effect of autoimmunity and the inability of macrophages to generate a cellular phenotype important for ß-cell regeneration. The experimental models described in this proposal will allow us to further study the macrophage-dependent ß-cell proliferation in mice (specific aims 1), to evaluate the ability of human-derived macrophages to induce ß- cell replication (specific aims 2), and to identify putative factors released by macrophages that are necessary for human ß-cell generation (specific aims 3). Immune therapy significantly reduces the autoimmune-associated ß-cell proliferation. Thus, additional therapeutic approaches that would stimulate ß-cell regeneration in the absence of autoimmune destruction may be needed for recovery of ß-cell mass. As a potential cell therapeutic approach, macrophages generated from patient's monocytes could be reprogrammed to promote ß-cell regeneration. This work is a high priority area as it is directly applicable to our full understanding and potential treatment of T1D.