Type I diabetes is characterized by the permanent loss of pancreatic insulin-producing beta cells. Our goal is to understand the mechanisms determining pancreatic beta cell mass, as a first step toward the development of regenerative therapies for diabetes. In collaboration with the BCBC Coordinating Center and members of the consortium, we will use transgenic mouse technology to examine the hypothesis that beta cells have a significant regenerative capacity, which is modulated by specific signals.
The specific aims are to: 1. Develop a system for regulated ablation of pancreatic beta cells. Our preliminary studies indicate that mice can recover from a pulse of beta cell ablation. We will characterize in detail the physiological and histological aspects of ablation and recovery, in order to understand the mechanisims of beta cell regeneration. 2. Determine the cellular origins of regenerating beta cells. We will employ genetic lineage tracing to definitely determine the contributions of stem cells and pre-existing beta cells to beta cell regeneration. 3. Characterize the signals that regulate beta cell mass. The relative importance of blood-borne signals will be determined, with emphasis on the role of insulin and glucose metabolism. In addition, we will assess the significance of beta cell dedifferentiation in vivo and in vitro. Insights from these studies will be applied to primary beta cell cultures, with the aim of improving yield, preventing dedifferentiation and minimizing cell death
| Annes, Justin P; Ryu, Jennifer Hyoje; Lam, Kelvin et al. (2012) Adenosine kinase inhibition selectively promotes rodent and porcine islet ?-cell replication. Proc Natl Acad Sci U S A 109:3915-20 |
| Blum, Barak; Hrvatin, Siniša; Schuetz, Christian et al. (2012) Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3. Nat Biotechnol 30:261-4 |
| Chen, Chen Amy; Carolan, Peter J; Carolan, Peter C et al. (2012) In vivo screening for secreted proteins that modulate glucose handling identifies interleukin-6 family members as potent hypoglycemic agents. PLoS One 7:e44600 |
| Borowiak, Malgorzata; Maehr, René; Chen, Shuibing et al. (2009) Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells. Cell Stem Cell 4:348-58 |
| Brennand, Kristen; Melton, Doug (2009) Slow and steady is the key to beta-cell replication. J Cell Mol Med 13:472-87 |
| Borowiak, Malgorzata; Melton, Douglas A (2009) How to make beta cells? Curr Opin Cell Biol 21:727-32 |
| Granot, Zvi; Swisa, Avital; Magenheim, Judith et al. (2009) LKB1 regulates pancreatic beta cell size, polarity, and function. Cell Metab 10:296-308 |
| Anderson, William J; Zhou, Qiao; Alcalde, Victor et al. (2008) Genetic targeting of the endoderm with claudin-6CreER. Dev Dyn 237:504-12 |
