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Critical Role of Small Extracellular Vesicles in Diabetic Coronary VascularDysfunction and Diabetic Ischemic Heart Failure efforts

Award Number: R01HL158612
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Critical Role of Small Extracellular Vesicles in Diabetic Coronary VascularDysfunction and Diabetic Ischemic Heart Failure efforts - With continually improving reperfusion strategies, the overall mortality of AMI has been significantly reduced in non-diabetic patients. However, both the prevalence and severity of ischemic heart failure (IHF) continually escalate in patients with type 2 diabetes. Identifying risk factors, pathological mechanisms, and effective interventions blocking diabetic exacerbation of IHF are urgently needed. Endothelial injury and resultant coronary microvascular dysfunction (CMD) are the hallmarks of diabetic cardiovascular complications, hindering adequate reperfusion despite successful recanalization. Clarifying mechanisms responsible for diabetic CMD and identifying effective interventions improving coronary circulation are essential in reducing diabetic IHF exacerbation. Research in the past decade has increased understanding of the roles adipocytes (ADp) play in health and disease. Functional ADp are critical in maintaining systemic metabolic hemostasis, whereas ADp dysfunction is one of the most recognized pathogenic factors leading to type 2 diabetes. A complete understanding of the molecular mechanisms mediating the communication between adipose tissue and heart will undoubtedly help the development of effective therapies against diabetic cardiovascular death. Extracellular vesicles, particularly exosomes (Exo), are increasingly recognized as systemic messengers mediating inter- cellular/inter-organ communication. Evidence from our recently published work and additional preliminary data strongly suggest that GRK5-induced coronary microcirculatory endothelial cells (CMEC) adiponectin receptor 1 (AdipoR1) phosphorylation is responsible for attenuated ADp-derived Exo (ADp-Exo) protective signaling and increased cytotoxic ADp-Exo uptake in diabetic CMEC, contributing to diabetic exacerbation of CMD and IHF. Targeting the GRK5-AdipoR1 system may be a novel therapeutic intervention against diabetic CMD, ultimately protecting the heart against IHF. This novel hypothesis will be rigorously investigated in 3 specific aims. Utilizing genetic gain- and loss-of-function approaches, Specific Aim 1 will test a hypothesis that diabetes-induced CMEC AdipoR1 phosphorylation blocks ADp-Exo mediated vasculoprotection, contributing to diabetic CMD and IHF exacerbation. Specific Aim 2 will test a novel hypothesis that diabetic AdipoR1 phosphorylation and resultant endocytosis promotes CMEC uptake of cytotoxic ADp-Exo via adiponectin (on ADp-Exo surface) interaction with AdipoR1 (expressed in CMEC). Specific Aim 3 will determine whether 1) EC AdipoR1 phosphorylation mediates diabetic ADp-Exo induced CMD and IHF, and 2) blocking EC AdipoR1 phosphorylation is effective in protecting diabetes-exacerbated CMD and IHF. Successful completion of these studies will reveal a novel molecular mechanism responsible for the diabetic exacerbation of cardiovascular injury, and potentially identify novel therapy against CMD and post-MI remodeling in diabetic patients. Moreover, successful completion of the proposed studies may have broader implications in the development of other diseases involving Exo, as our work will help to fill a knowledge gap concerning cell/tissue-selective recognition of circulating Exo.


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 = $0 )
2025	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	1/30/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $359,006 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	5	4/16/2024	NON-COMPETING CONTINUATION	$329,700
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	5	6/21/2024	NON-COMPETING CONTINUATION	$29,306
														Subtotal = $359,006

Issue Date FY: 2023 ( Subtotal = $366,335 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	002	4	4/6/2023	NON-COMPETING CONTINUATION	$366,335
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	3	1/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$390,549
2023	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	2	1/19/2023	NON-COMPETING CONTINUATION	-$390,549
2023	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	003	1	5/15/2023	NEW	$0
														Subtotal = $366,335

Issue Date FY: 2022 ( Subtotal = $390,549 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	2	5/3/2022	NON-COMPETING CONTINUATION	$390,549
														Subtotal = $390,549

Issue Date FY: 2021 ( Subtotal = $404,550 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	7/5/2021	NEW	$404,550
														Subtotal = $404,550

Grand Total All Awards = $1,520,440

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Critical Role of Small Extracellular Vesicles in Diabetic Coronary VascularDysfunction and Diabetic Ischemic Heart Failure efforts

Award Number: R01HL158612

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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