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Targeting Adiponectin for Cardioprotection in the Ischemic Heart

Award Number: R01HL096686
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2010
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Targeting Adiponectin for Cardioprotection in the Ischemic Heart - Cardiovascular disease is the leading cause of morbidity and mortality in patients with obesity/type 2 diabetes. Strict glycemic control in recent large-scale clinical trials failed to demonstrate cardiovascular mortality benefit in type 2 diabetic patients. Novel strategies capable of protecting the heart against diabetes-exacerbated post- myocardial infarction (MI) remodeling are urgently needed. 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 obesity/type 2 diabetes. The cardiomyocyte (CM) is the most important cell type maintaining heart function. Its failure is the direct cause of diabetic cardiac death. Complete understanding of the molecular mechanisms mediating the adverse communication between diabetic ADp (the culprit of obesity-induced diabetes) and diabetic CM (the victim in which injury most significantly contributes to diabetic cardiovascular death) will certainly help development of effective therapies against diabetic cardiovascular death. Extracellular vesicles, particularly exosomes (Exo), are critical agents in remote organ communication. Our most recently published study demonstrates for the first time that diabetes causes significant ADp Exo dysfunction, switching ADp-Exo from cargo-carrying cardioprotective molecules to vehicles delivering cardiotoxic molecules from ADp to CM, critically contributing to diabetic cardiac injury. Our preliminary data further demonstrate that diabetic CM lose protective response to non-diabetic ADp-Exo, while uptake of diabetic ADp-Exo significantly increases. Several in vivo and in vitro experiments strongly suggest that diabetes-induced CM adiponectin receptor-1 (AdipoR1) phosphorylation is a central mechanism switching Exo-mediated ADp-CM communication from a receptor/intracellular salvage kinase activation system to a vehicle delivering toxic ADp-Exo into diabetic CM, enhancing post-MI remodeling and accelerating heart failure. This novel hypothesis will be rigorously investigated by utilizing multiple tissue-specific genetically manipulated animals and pharmacological interventions. Specific Aim 1 will clarify the critical role of diabetes-induced CM AdipoR1 phosphorylation in blocking ADp-Exo mediated cardioprotection. Specific Aim 2 will test a hypothesis that diabetes-induced CM AdipoR1 phosphorylation promotes toxic ADp-Exo endocytosis. Specific Aim 3 will prove a concept that diabetes- induced CM AdipoR1 phosphorylation plays a causative role in diabetic ADp-Exo mediated cardiac injury. Successful completion of these studies will reveal a novel molecular mechanism responsible for diabetic exacerbation of cardiac injury, and potentially identify novel therapy against 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: 2024 ( Subtotal = $390,229 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	12	11/6/2023	NON-COMPETING CONTINUATION	$390,229
														Subtotal = $390,229

Issue Date FY: 2023 ( Subtotal = $390,229 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	11	2/11/2023	NON-COMPETING CONTINUATION	$39,023
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	11	1/12/2023	NON-COMPETING CONTINUATION	$351,206
														Subtotal = $390,229

Issue Date FY: 2022 ( Subtotal = $396,284 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	10	11/5/2021	NON-COMPETING CONTINUATION	$356,490
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	002	10	6/8/2022	NON-COMPETING CONTINUATION	$39,611
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	10	4/7/2022	NON-COMPETING CONTINUATION	$0
2022	2019	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	003	8	9/26/2022	NON-COMPETING CONTINUATION	$183
														Subtotal = $396,284

Issue Date FY: 2021 ( Subtotal = $398,357 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	004	9	6/28/2021	COMPETING CONTINUATION	$24,520
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	9	12/20/2020	COMPETING CONTINUATION	$358,521
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	002	9	6/11/2021	COMPETING CONTINUATION	$39,836
2021	2019	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	8	12/18/2020	NON-COMPETING CONTINUATION	$0
2021	2019	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	003	8	6/28/2021	NON-COMPETING CONTINUATION	-$24,520
														Subtotal = $398,357

Issue Date FY: 2019 ( Subtotal = $389,999 )
2019	2019	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	8	3/21/2019	NON-COMPETING CONTINUATION	$389,999
														Subtotal = $389,999

Issue Date FY: 2018 ( Subtotal = $390,001 )
2018	2018	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	7	8/2/2018	NON-COMPETING CONTINUATION	$7,801
2018	2018	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	7	3/19/2018	NON-COMPETING CONTINUATION	$382,200
														Subtotal = $390,001

Issue Date FY: 2017 ( Subtotal = $396,739 )
2017	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	6	3/24/2017	NON-COMPETING CONTINUATION	$396,739
														Subtotal = $396,739

Issue Date FY: 2016 ( Subtotal = $397,260 )
2016	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	5	5/20/2016	COMPETING CONTINUATION	$397,260
														Subtotal = $397,260

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2013	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	4	5/14/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $365,211 )
2013	2013	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	4	6/10/2013	NON-COMPETING CONTINUATION	$365,211
														Subtotal = $365,211

Issue Date FY: 2012 ( Subtotal = $383,625 )
2012	2012	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	3	4/10/2012	NON-COMPETING CONTINUATION	$383,625
														Subtotal = $383,625

Issue Date FY: 2011 ( Subtotal = $387,375 )
2011	2011	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	2	5/20/2011	NON-COMPETING CONTINUATION	$387,375
														Subtotal = $387,375

Issue Date FY: 2010 ( Subtotal = $386,667 )
2010	2010	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	1	4/12/2010	NEW	$417
2010	2010	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	4/2/2010	NEW	$386,250
														Subtotal = $386,667

Grand Total All Awards = $4,671,976

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Targeting Adiponectin for Cardioprotection in the Ischemic Heart

Award Number: R01HL096686

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2010

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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