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The role of Ngn3 to induce beta cell neogenesis and signals that activate the Ngn3 gene expression (FWOTM622)

Current diabetes research focuses on regenerative medicine as a cure for type 1 diabetes, by replacing or regenerating the insulin producing beta cell mass. One strategy is to generate new beta cells in vitro that can be used for transplantation. Another strategy is to induce beta cell regeneration in vivo. These strategies entirely depend on identifying the key mechanism and factors that allow beta cell differentiation and proliferation in the developing and adult pancreas.
In the developing pancreas, all of the endocrine cell types originate from an endocrine progenitor cell, expressing the transcription factor Neurogenin3 (Ngn3). In the embryonic, fetal and neonatal pancreas, beta cells are generated by differentiation from these progenitors and by proliferation. However, adult beta cell regeneration under normal physiological conditions does no longer involve differentiation, but depends entirely on slow selfduplication, characterized by a refractory period, preventing beta cell from serially dividing from one round to the next under normal condition.
Our group has reported the presence of a Ngn3 positive progenitor in the adult pancreas in the injury model of partial pancreatic duct ligation (PDL), in which beta cell mass is increased, as a result of beta cell neogenesis and proliferation. For this project we would like to evaluate the role of Ngn3 expression in the formation of new beta cells by differentiation and proliferation during regeneration. So far it is still unclear how the Ngn3 expression is activated in both developing and regenerating pancreas. We propose Signal Transducer and Activator of Transcription 3 (Stat3) alone or in cooperation with Delta-notch signaling as possible mechanism that may activate the expression of this pro-endocrine transcription factor.
Date:1 Oct 2012  →  30 Sep 2016