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

Award Number: UC4DK104209
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Beta-cell Regeneration by Islet Cell Type Interconversion: Exploiting Islet Cell Plasticity for Diabetes Recovery - DESCRIPTION (provided by applicant): 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 β 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 α 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 α 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: Aim1: Pathways and factors promoting/facilitating α cell reprogramming in mice and human Aim2: Pathways and factors promoting/facilitating δ cell reprogramming in mice and human Aim3: In vivo (whole body) tissue screening to identify new cell sources with high plasticity potential to convert toward the β cell phenotype Description of Aims 1 and 2: We previously reported that α cells do reprogram to insulin production after β cell loss in adult mice. We have now discovered (MS under revision) that δ cells efficiently reprogram to insulin production after total β cell loss in prepubescent mice, leading to 100% diabetes recovery. We plan to study: 1- What are the instructive signals and which signaling pathways coordinate α cell and - δ cell conversion? 2- Why δ cell conversion is temporally restricted to young mice, while α cell conversion only occurs after puberty? 3- Are α cell and δ cell conversion mechanisms mutually exclusive? 4- Can in vivo α cell and δ cell conversions be facilitated by means of compounds mimicking the effect of instructive signals? 5- Are human islets endowed with cell plasticity capabilities? How diabetic conditions influence i) the capacity of human/mouse α cell and δ cells to reprogram, and ii) the maintenance of the β cell phenotype? Description of Aim 3: Given the potential clinical impact of cell reprograming considered broadly, we also plan to explore other target cell types for their capacity for trans-fating into a β cell-like phenotype. We plan to study: 1- What tissues are susceptible of undergoing cell reprogramming? What are the optimal conditions for cell reprogramming in situ? Would ectopic extra-pancreatic beta-like cells function properly? 2- Can transplantable functional insulin-producing cells be obtained ex vivo from patient-derived primary cells?


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2020 ( Subtotal = -$4 )
2020	2014	UNIVERSITE DE GENEVE	RUE GENERAL-DUFOUR 24	GENEVE	GE	1204		CHE	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	10/1/2019	NEW	-$4
														Subtotal = -$4

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2014	UNIVERSITE DE GENEVE	RUE GENERAL-DUFOUR 24	GENEVE	GE	1204		CHE	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/24/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $2,415,571 )
2014	2014	UNIVERSITY OF GENEVA SCHOOL OF MEDICINE	1 RUE MICHEL-SERVET	GENEVA				CHE	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/12/2014	NEW	$2,415,571
														Subtotal = $2,415,571

Grand Total All Awards = $2,415,567

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

Award Number: UC4DK104209

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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