Avviso di Seminario: Dr. Amedeo Vetere - "Chemical methods to induce beta-cell proliferation" , A1 (piano III, ed. C11)

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Data evento
Data inizio evento: 
22/09/2016 - 11:00
Data fine evento: 
22/09/2016 - 12:00
Data pubblicazione evento
Pubblicato il: 
20/09/2016

 

Avviso di seminario

 

Amedeo Vetere, Ph.D.

Broad Institute of MIT and Harvard Center for the Science of Therapeutics
140 Main St., Cambridge MA 02142 (USA)
avetere@broadinstitute.org

 

Chemical methods to induce beta-cell proliferation


Restoring functional β-cell mass is an important therapeutic goal for both type 1 and type 2 diabetes. While proliferation of existing β-cells is the primary means of β-cell replacement in rodents, it is unclear whether a similar principle applies to humans, as human β-cells are remarkably resistant to stimulation of division. We have shown that 7-(5-Deoxy-β-D-ribofuranosyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5-iodotubercidin, 5-IT), an annotated adenosine kinase inhibitor previously reported to increase proliferation in rodent and porcine islets, strongly and selectively increases human β-cell proliferation in vitro and in vivo. Remarkably, 5-IT also increased glucose-dependent insulin secretion after prolonged treatment. Kinome profiling revealed 5-IT to be a potent and selective inhibitor of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) and cell division cycle-like kinase families. Induction of β-cell proliferation by either 5-IT or 7-MeO-1-Me-9H-pyrido[3,4-b]-indole (harmine), another natural product DYRK1A inhibitor, was suppressed by coincubation with the calcineurin inhibitor FK506, suggesting involvement of DYRK1A and nuclear factor of activated T cells signaling. Gene expression profiling in whole islets treated with 5-IT revealed induction of proliferation- and cell cycle-related genes, suggesting that true proliferation is induced by 5-IT. Furthermore, 5-IT promotes β-cell proliferation in human islets grafted under the kidney capsule of NOD-scid IL2Rg(null) mice. These results point to inhibition of DYRK1A as a therapeutic strategy to increase human β-cell proliferation.

Ultimo aggiornamento: 20-09-2016 - 13:31
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