Inhibition of TGFβ Signaling Does Not Improve the Limited Proliferative Response to Nkx6.1 Or Pdx-1 Overexpression in Aged Rat Islets
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A deficiency in functional pancreatic beta-cells is a defining feature in type 1 and type 2 diabetes. The development of therapeutic strategies for replacement and regeneration of beta-cell mass is a key objective of current diabetes research. The Newgard lab has had a particular focus in exploring novel beta-cell replication pathways in order to identify targets that enhance beta-cell proliferation, survival, and function. The beta-cell developmental transcription factors Nkx6.1 and Pdx-1 each have a profound proliferative effect when overexpressed in young rat islets in vitro. The unique ability of these factors and the pathways that they control to expand functional beta-cell mass while either being neutral or positive for other key functions (survival, insulin secretion) encourages further studies to better elucidate candidate target genes within these pathways.
A major limitation of the research to date is that Nkx6.1 and Pdx-1 only exert their proliferative effects in young (2 months) rodent islets and not in old (8-10 months) rodent islets. Moreover, these factors are only weakly active in human islets, most of which come from middle-aged donors. Nkx6.1 and Pdx-1 engage pathways that are upstream of the core cell cycle machinery and that have the potential to be stimulated in a beta-cell specific manner, but use of this approach will depend on a better understanding of the differences between human and rodent islets, which may be modeled by the differences between old and young rat islets.
Rosa, Taylor (2015). Inhibition of TGFβ Signaling Does Not Improve the Limited Proliferative Response to Nkx6.1 Or Pdx-1 Overexpression in Aged Rat Islets. Master's thesis, Duke University. Retrieved from https://hdl.handle.net/10161/9980.
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