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Project Abstracts - CTAR

Beta-cell Regeneration by Islet Cell Type Interconversion: Exploiting Islet Cell Plasticity for Diabetes Recovery

Contact PI: Pedro Herrera, PhD, University of Geneva (UC4 DK104209)

Kenichiro Furuyama, MD, PhD, co-Investigator, University of Geneva
Fabrizio Thorel, PhD, co-Investigator, University of Geneva

 

Summary of Project Abstract & Publications

Start Date: September 30, 2014

 

Abstract

 

The overall goal of this proposal is to identify means for improving β cell regeneration in the adult pancreas. With previous help of NIH/NIDDK funding we developed a transgenic model of inducible total or partial β cell ablation (termed RIP-DTR). We have reported that in these mice there is spontaneous reconstitution of new ? cells from heterologous (i.e. non-β cells after near-total β cell loss. The RIP-DTR model has revealed an unsuspected degree of cellular plasticity in the pancreas of juvenile and adult mice, including aged individuals, regarding the spontaneous inherent capacity of islet α cells and δ cells to switch to insulin production upon β cell loss. During the next 5 years we want to address the following fundamental questions: 1. What is (are) the signal(s) driving β cell reprogramming upon near-total β cell ablation? 2. Can the α-cell to β-cell conversion be fostered? Why only a small fraction of β cells engages into conversion? What is the nature of the epigenetic modifications in reprogrammed β cells? 3. Can human α-cells reprogram to insulin production? 4. What is the influence of ageing on islet cell plasticity?   5. Can other islet cells, i.e. besides α cells, reprogram to insulin production? Specifically, the proposed aims are as follows: Aim 1: Pathways and factors promoting/facilitating α cell reprogramming in mice and human Aim 2: Pathways and factors promoting/facilitating δ cell reprogramming in mice and human Aim 3: In vivo (whole body) tissue screening to identify new cell sources with high plasticity potential to convert toward the β cell phenotype.

Publications