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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Date

2015

Authors

Rosa, Taylor

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Newgard, Christopher B

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Abstract

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.

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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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