We propose the generation of a transgenic model of rapid inducible diabetes. The major aim of this proposal is to determine the origin of insulin-producing beta-cells in adult mice. In these animals, complete, or partial, selective destruction of pancreatic beta-cells will be induced, either during development, during postnatal growth or in adults, upon administration of an inducer drug. These animals will not be engineered to study the pathogenesis of Type I diabetes and the autoimmune mechanisms, nor inflammation;rather, they will be useful to accurately assess islet (beta-cell) neoformation in adult pancreas during the regeneration process that should follow the treatment with the inducer agent. They will also be used in reconstitution assays to determine the differentiation potential of injected stem / progenitor cells, whether i.v. or directly into the pancreas, derived either from pancreatic or extra-pancreatic tissues (e. g. hepatic, neural or hematopoietic stem cells, or ES cell clones). Incidentally, this transgenic model will represent a unique tool to study the involvement of beta-cells in pancreas homeostasis, besides their role of producing insulin.
The specific aims are: i) generation of a transgenic model of beta-cell ablation, which will be useful to ii) study beta-cell regeneration and to iii) perform in vivo clonogenic reconstitution assays of transplanted cells. Beyond the basic processes of organ growth and maintenance, this study may have implications for cell replacement therapy in diabetes and for all ethical issues related to the use of embryonic or adult stem cells. Once generated, these transgenic strains will be put into the """"""""public"""""""" Beta Cell Biology Consortium (BCBC) mouse repository, so as to become available to the broad scientific community, as we have already done with other transgenic mice that we produced in the past
