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Inhibition of TGFβ Signaling Does Not Improve the Limited Proliferative Response to Nkx6.1 Or Pdx-1 Overexpression in Aged Rat Islets

dc.contributor.advisor Newgard, Christopher B Rosa, Taylor 2015-05-12T20:50:12Z 2015-10-03T04:30:06Z 2015
dc.description.abstract <p>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.</p><p>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.</p>
dc.subject Cellular biology
dc.subject Endocrinology
dc.subject Pharmacology
dc.subject beta-cell
dc.subject Islet
dc.subject Nkx6.1
dc.subject pancreatic
dc.subject Pdx-1
dc.subject TGF-beta
dc.title Inhibition of TGF&#946; Signaling Does Not Improve the Limited Proliferative Response to Nkx6.1 Or Pdx-1 Overexpression in Aged Rat Islets
dc.type Master's thesis
dc.department Pharmacology
duke.embargo.months 4

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