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HB-EGF as a central regulator of pancreatic beta-cell proliferation

Award Number: R01DK058096
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2001
PERIOD OF PERFORMANCE END DATE: 06/30/2022

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HB-EGF as a central regulator of pancreatic beta-cell proliferation - One in ten adults will have diabetes by 2040. Both type 1 (T1D) and type 2 diabetes (T2D) are characterized by a reduction in functional β-cell mass. Our overarching hypothesis is that a precise understanding of the molecular mechanisms controlling human β-cell proliferation may provide novel strategies to 1.) expand functional β-cell mass prior to islet transplantation in T1D; and 2.) prevent or delay the development of T2D in individuals at risk. The specific objective of this project is to elucidate the role of heparin-binding EGF-like growth factor (HB-EGF) in the control of β-cell proliferation. Previous findings and recent data from our group provide a strong basis for this proposal and include: 1.) HB-EGF is a potent human β-cell mitogen; 2.) HB-EGF expression in human islets correlates with Body Mass Index; 3.) β-cell proliferation in response to glucose and other β-cell mitogens is blocked by inhibition of HB-EGF or EGF receptor (EGFR) signaling; 4.) somatostatin (SST) blocks HB-EGF-induced β-cell proliferation. These data led us to formulate the hypothesis that autocrine/paracrine HB-EGF signaling through EGFR in β-cells integrates positive and negative signals to regulate β-cell proliferation. This hypothesis will be tested by: 1.) Investigating whether glucose and other mitogens promote β-cell proliferation via HB-EGF-dependent EGFR activation in isolated rodent and human islets. Then the mechanism involved in metalloproteinase-dependent shedding of HB-EGF from its membrane-bound precursor will be determined using genetic and pharmacological approaches. 2.) Elucidating the mechanisms by which SST and other inhibitory G protein-coupled receptors (GPCR) dampen glucose-induced EGFR signaling in isolated rodent and human islets. In particular, whether this is mediated by direct interaction between inhibitory GPCRs and the EGFR will be investigated in collaboration with M. Bouvier at the Institut de Recherche en Immunologie et Cancérologie. 3.) Ascertaining the role of HB-EGF in β-cell compensation using a conditional β-cell specific knockout approach in mice in response to high-fat feeding and gestation. The importance of HB-EGF for human β-cell proliferation will be confirmed by transplanting HB-EGF-deficient juvenile human islets into exendin-4-treated immunodeficient mice, a model established by our collaborator A. Powers at Vanderbilt University. Dissecting the mode of regulation and mechanism of action of HB-EGF will provide important insights into the regulation of β-cell proliferation. From a therapeutic perspective, these findings may help design novel strategies to expand β-cell mass prior to islet transplantation in T1D and to maintain or expand functional β-cell mass in T2D.


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: 2023 ( Subtotal = $0 )
2023	2020	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTRAAL	QC			CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	12/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $221,682 )
2020	2020	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	6/25/2020	NON-COMPETING CONTINUATION	$221,682
														Subtotal = $221,682

Issue Date FY: 2019 ( Subtotal = $221,682 )
2019	2019	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	6/25/2019	NON-COMPETING CONTINUATION	$221,682
														Subtotal = $221,682

Issue Date FY: 2018 ( Subtotal = $221,682 )
2018	2018	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	6/4/2018	NON-COMPETING CONTINUATION	$221,682
														Subtotal = $221,682

Issue Date FY: 2017 ( Subtotal = $221,682 )
2017	2017	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	3840 RUE SAINT-URBAIN	MONTREAL	PQ	H2W 1T8		CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	6/26/2017	COMPETING CONTINUATION	$221,682
														Subtotal = $221,682

Issue Date FY: 2015 ( Subtotal = $228,168 )
2015	2015	UNIVERSITY OF MONTREAL HOSPITAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC				CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	7/10/2015	SUPPLEMENT FOR EXPANSION	$15,552
2015	2015	UNIVERSITY OF MONTREAL HOSPITAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC				CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	7/15/2015	NON-COMPETING CONTINUATION	$212,616
														Subtotal = $228,168

Issue Date FY: 2014 ( Subtotal = $212,616 )
2014	2014	UNIVERSITY OF MONTREAL HOSPITAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC				CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	6/12/2014	NON-COMPETING CONTINUATION	$212,616
														Subtotal = $212,616

Issue Date FY: 2013 ( Subtotal = $205,176 )
2013	2013	HOTEL-DIEU HOSPITAL MONTREAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC				CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	6/20/2013	EXTENSION WITH OR WITHOUT FUNDS	$205,176
														Subtotal = $205,176

Issue Date FY: 2012 ( Subtotal = $212,616 )
2012	2012	HOTEL-DIEU HOSPITAL MONTREAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC				CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	4/9/2012	COMPETING CONTINUATION	$212,616
														Subtotal = $212,616

Issue Date FY: 2010 ( Subtotal = $203,486 )
2010	2010	HOTEL-DIEU HOSPITAL MONTREAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC				CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	5/27/2010	NON-COMPETING CONTINUATION	$203,486
														Subtotal = $203,486

Issue Date FY: 2009 ( Subtotal = $205,541 )
2009	2009	HOTEL-DIEU HOSPITAL MONTREAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC				CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/28/2009	NON-COMPETING CONTINUATION	$205,541
														Subtotal = $205,541

Issue Date FY: 2007 ( Subtotal = $209,736 )
2007	2007	HOTEL-DIEU HOSPITAL MONTREAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC		00000		CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	5/1/2007	NON-COMPETING CONTINUATION	$209,736
														Subtotal = $209,736

Issue Date FY: 2006 ( Subtotal = $216,000 )
2006	2006	HOTEL-DIEU HOSPITAL MONTREAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC		00000		CAN	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/10/2006	COMPETING CONTINUATION	$216,000
														Subtotal = $216,000

Issue Date FY: 2004 ( Subtotal = $262,500 )
2004	2004	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/3/2004	NON-COMPETING CONTINUATION	$262,500
														Subtotal = $262,500

Issue Date FY: 2003 ( Subtotal = $262,500 )
2003	2003	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/27/2003	NON-COMPETING CONTINUATION	$262,500
														Subtotal = $262,500

Issue Date FY: 2002 ( Subtotal = $262,500 )
2002	2002	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/20/2002	NON-COMPETING CONTINUATION	$262,500
														Subtotal = $262,500

Issue Date FY: 2001 ( Subtotal = $291,485 )
2001	2001	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/15/2001	NEW	$291,485
														Subtotal = $291,485

Grand Total All Awards = $3,659,052

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HB-EGF as a central regulator of pancreatic beta-cell proliferation

Award Number: R01DK058096

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2001

PERIOD OF PERFORMANCE END DATE: 06/30/2022

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