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Metabolic crosstalks in regulation of beta-cell stress response and adaptation

Award Number: R01DK078081
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: 02/01/2008
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Metabolic crosstalks in regulation of beta-cell stress response and adaptation - Abstract Glucose metabolism generates important signals that regulate several facets of β-cell health, including insulin secretion, proliferation, survival, and differentiation. We have found that the TCA cycle enzyme pyruvate carboxylase (PC), which promotes metabolic signals that regulate insulin secretion, has previously unappreciated roles in β-cell stress mitigation by promoting urea cycle activity and de novo glutathione (GSH) synthesis. These PC-directed pathways can promote a dual defense mechanism, whereby nitric oxide (NO) synthesis from arginine is reduced as arginine is utilized for ureagenesis and antioxidant capacity is increased by de novo GSH synthesis in the face of diabetes-related stress stimuli. Both pathways receive input from glucose through PC activity and are modulated by phosphorylation of BAD, a GK binding and activating protein that drives a broad β-cell protective program. This renewal application addresses key questions that stem from these findings: What are the molecular mechanistic components of this PC-driven β-cell protective program and how do they contribute to β- cell mass dynamics? We will address these questions in two aims. First, we will dissect the downstream effectors of the urea cycle pathway that are required for β-cell protection. Our prediction is that beyond changing the balance between urea and NO production, urea cycle activation provides biosynthetic intermediates that promote growth, including ornithine and polyamines. We will also examine how glucose is connected to these pathways using metabolomics and metabolic tracing studies combined with genetic and pharmacologic perturbations of these pathways. Similarly, we will examine the route for glucose to GSH synthesis and how this antioxidant mechanism factors into PC-mediated protection. We will then test the relevance of these pathways in protecting donor islets in a marginal mass islet transplantation model (Aim 1). Second, we will test the contributions of these pathways to β-cell mass adaptation in response to high fat diet (HFD) using two complementary approaches; a β-cell-specific PC knockout mouse model treated with HFD and assessing the response of donor islet grafts to (HFD) treatment of transplanted mice (Aim 2). These studies will provide an integrated picture of the pathways connecting phospho-BAD, GK and PC activation to β-cell stress response and adaptation. In the fullness of time, understanding these connections will yield valuable insights into the most effective strategies to capture and mimic the protective aspects of glucose signaling for preservation/restoration of functional β-cell mass.


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: 2025 ( Subtotal = $493,019 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	6/12/2025	NON-COMPETING CONTINUATION	$49,301
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	3/3/2025	NON-COMPETING CONTINUATION	$443,718
														Subtotal = $493,019

Issue Date FY: 2024 ( Subtotal = $468,839 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	12	5/3/2024	NON-COMPETING CONTINUATION	$29,302
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	12	3/22/2024	NON-COMPETING CONTINUATION	$439,537
2024	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	10/26/2023	COMPETING CONTINUATION	$2,281
2024	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	10/26/2023	NON-COMPETING CONTINUATION	-$2,281
														Subtotal = $468,839

Issue Date FY: 2023 ( Subtotal = $507,874 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	2/22/2023	COMPETING CONTINUATION	$507,874
														Subtotal = $507,874

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	5/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/10/2021	NON-COMPETING CONTINUATION	$0
2021	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	3/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $417,909 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/20/2020	NON-COMPETING CONTINUATION	$417,909
														Subtotal = $417,909

Issue Date FY: 2019 ( Subtotal = $416,407 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/28/2019	NON-COMPETING CONTINUATION	$416,407
														Subtotal = $416,407

Issue Date FY: 2018 ( Subtotal = $412,730 )
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	3/6/2018	NON-COMPETING CONTINUATION	$371,457
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	4/30/2018	NON-COMPETING CONTINUATION	$41,273
														Subtotal = $412,730

Issue Date FY: 2017 ( Subtotal = $410,526 )
2017	2017	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	3/7/2017	NON-COMPETING CONTINUATION	$369,473
2017	2017	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	6/14/2017	NON-COMPETING CONTINUATION	$41,053
														Subtotal = $410,526

Issue Date FY: 2016 ( Subtotal = $410,658 )
2016	2016	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/16/2016	COMPETING CONTINUATION	$410,658
														Subtotal = $410,658

Issue Date FY: 2012 ( Subtotal = $337,145 )
2012	2012	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/6/2012	NON-COMPETING CONTINUATION	$33,714
2012	2012	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/5/2012	NON-COMPETING CONTINUATION	$303,431
														Subtotal = $337,145

Issue Date FY: 2011 ( Subtotal = $337,145 )
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/2/2011	NON-COMPETING CONTINUATION	$30,649
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/10/2011	NON-COMPETING CONTINUATION	$306,496
														Subtotal = $337,145

Issue Date FY: 2010 ( Subtotal = $340,551 )
2010	2010	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/29/2010	NON-COMPETING CONTINUATION	$340,551
														Subtotal = $340,551

Issue Date FY: 2009 ( Subtotal = $343,991 )
2009	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/5/2009	NON-COMPETING CONTINUATION	$34,400
2009	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/30/2009	NON-COMPETING CONTINUATION	$309,591
														Subtotal = $343,991

Issue Date FY: 2008 ( Subtotal = $343,991 )
2008	2008	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/15/2008	NEW	$343,991
														Subtotal = $343,991

Grand Total All Awards = $5,240,785

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Metabolic crosstalks in regulation of beta-cell stress response and adaptation

Award Number: R01DK078081

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: 02/01/2008

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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