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Targeting ADAM17 activity for correction of vascular insulin resistance in type 2 diabetes

Award Number: R01HL151384
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Targeting ADAM17 activity for correction of vascular insulin resistance in type 2 diabetes - PROJECT SUMMARY/ABSTRACT Vascular insulin resistance is a hallmark of type 2 diabetes (T2D) and dampening of insulin-induced vasodilation is its primary consequence. Notably, in T2D, reduced insulin-stimulated vasodilation and blood flow to tissues such as skeletal muscle significantly limits glucose uptake and contributes to impaired glucose control. A detailed understanding of the precipitating factors and mechanisms underlying the defects in vasodilator actions of insulin is critical for the development of therapeutic strategies aimed at improving glycemic control and protecting against cardiovascular disease. Based on our prior work and most recent and exciting preliminary data, we propose the novel hypothesis that ADAM17-mediated shedding of the insulin receptor alpha (IRα) from endothelial cells impairs insulin-stimulated vasodilation in T2D. We further propose that the increased activity of endothelial ADAM17 is attributed to protein kinase-C (PKC) activation and subsequent externalization of phosphatidylserine (PS) to the outer leaflet of the cell membrane, which serves to guide ADAM17 to its targeted substrates. As exogenous PS is a competitive inhibitor of ADAM17 sheddase activity, we will also determine the efficacy of oral administration of PS for restoring vascular insulin sensitivity in T2D patients. We will test our innovative hypotheses with gain- and loss-of-function genetic-manipulation experiments in human cultured endothelial cells, in isolated resistance arteries harvested from patients undergoing abdominal surgery, and in patients with T2D. Experimental results will determine the role of PS externalization-ADAM17 activation-IRα shedding as a mechanism impairing the vasodilatory actions of insulin in T2D. Specifically, in Aim 1, we will determine the mechanism by which PKC causes the externalization of PS and whether PS externalization is needed for PKC-dependent activation of ADAM17 in endothelial cells. Next, in Aim 2, we will determine the role of ADAM17 activity in IRα shedding and subsequent impairment of insulin-stimulated vasodilation in T2D. Finally, in Aim 3, we will perform a randomized double-blind clinical trial to determine the therapeutic efficacy of oral administration of the competitive inhibitor of ADAM17 sheddase activity, PS, on insulin-stimulated leg blood flow in patients with T2D. Our team is poised to move cardiovascular and diabetes research forward with a project that will exert a sustained, powerful impact across a number of levels of inquiry that are novel conceptually, mechanistically, methodologically, and therapeutically. Indeed, this proposal represents a paradigm shift from our current mechanistic understanding of vascular insulin resistance. Targeting ADAM17 activation holds extraordinary promise for correcting vascular insulin resistance and ultimately preventing/treating T2D-associated metabolic and cardiovascular diseases.


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 = $613,392 )
2025	2025	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	5	3/26/2025	NON-COMPETING CONTINUATION	$613,392
														Subtotal = $613,392

Issue Date FY: 2024 ( Subtotal = $667,915 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	4	6/21/2024	NON-COMPETING CONTINUATION	$54,523
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	4	2/26/2024	NON-COMPETING CONTINUATION	$613,392
														Subtotal = $667,915

Issue Date FY: 2023 ( Subtotal = $681,547 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	3	2/10/2023	NON-COMPETING CONTINUATION	$681,547
														Subtotal = $681,547

Issue Date FY: 2022 ( Subtotal = $681,547 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	2	5/31/2022	NON-COMPETING CONTINUATION	$68,155
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	2	2/9/2022	NON-COMPETING CONTINUATION	$613,392
														Subtotal = $681,547

Issue Date FY: 2021 ( Subtotal = $679,426 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	1	2/25/2021	NEW	$611,483
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	1	6/23/2021	NEW	$67,943
														Subtotal = $679,426

Grand Total All Awards = $3,323,827

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Targeting ADAM17 activity for correction of vascular insulin resistance in type 2 diabetes

Award Number: R01HL151384

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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