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Sub-cellular Targeting of Endothelial ROS in Myocardial Ischemia

Award Number: R56HL133624
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Sub-cellular Targeting of Endothelial ROS in Myocardial Ischemia - renewal application is based on the novel findings that reduction in mito-ROS, using genetic manipulation and/or nanoparticle drugs, improve survival and proliferation of coronary EC and help recover cardiac function in a post-myocardial infarct (MI) animal model and human atrial tissue. Preliminary findings in the current application demonstrate that reduction of mito-ROS using transgene (MnSOD) and nanodrugs (JP4-039, XJB5-131) induce mitochondrial complex I biogenesis (proteomic and phosphoproteomic data) and oxidative phosphorylation (Ox-Phos) in EC resulting in coronary angiogenesis cardiac function recovery in post-MI heart. This innovative EC, like most tumor cells, utilizes anerobic glycolysis as a major (85%) source of ATP Thus, the shift from less- efficient energy production system glycolysis (2 ATP/glucose molecule), to a more efficient Ox-Phos (34-36 ATP/glucose) may provide critical energy support to EC needed during ischemia (low glucose, oxygen). Here, we propose to examine a novel overarching hypothesis that modulation of mito-ROS improves production, while EC mitochondria are mostly involved in dNTP biosynthesis. Δψm and ‘super-complex’ (SC) formation resulting in efficient electron transport chain (ETC) and Ox-Phos-mediated ATP generation in EC during ischemia. This shift from glycolysis to a more efficient mitochondrial Ox-Phos may provide resilience/survival to coronary EC during ‘energy crisis’ in myocardial ischemia. The therapeutic benefit of intervening on subcellular ROS level will be best realized by specific down regulation of mito-ROS in ECs that have been exposed to ischemia/hypoxia. This hypothesis will be fully tested in vivo using our novel EC-specific transgenic MnSOD (SOD-OE; mitochondrial antioxidant) animals and supported using mitochondria-specific nitroxide and nanoparticle antioxidant in large animal model (swine) and in coronary vessels from CVD patients undergoing cardiac surgery. We propose three Specific Aims. Aim 1: Elucidate the molecular mechanisms by which modulation of mitochondrial ROS protect coronary EC from oxidative stress and induce coronary angiogenesis during myocardial ischemia. Using SOD-VE transgenic animals and myocardial infarct-mimicking (LAD ligation) surgeries, Δψm, super-complex (SC) formation, oxygen consumption rate (OCR) versus extracellular acidification rate (ECAR), ATP synthesis, will be assessed. Aim 2: Determine the effects mitochondria-targeted MnSOD-mimetic (JP4-039, XJB-5-131) nanoparticles on post-infarct vessel density and recovery of cardiac function in mice and on chronic myocardial ischemia in large animals (swine). Aim 3: Elucidate the molecular mechanisms by which mitochondrial antioxidant nanoparticles (JP4-039/XJB-5-131) improve angiogenic potential of human coronary vessels (from cardiac surgery patients) ex vivo. This study using unique animal models, human atrial tissue, and mitochondria- specific antioxidant will provide novel insights into the mechanisms by which mito-ROS can improve EC survival and angiogenesis by recruiting mitochondria as an efficient energy generator during ischemia.


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: 2026 ( Subtotal = $0 )
2026	2022	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	000	5	3/20/2026	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	000	5	8/14/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $9,084 )
2023	2022	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	000	5	9/19/2023	COMPETING CONTINUATION	$9,084
														Subtotal = $9,084

Issue Date FY: 2022 ( Subtotal = $613,235 )
2022	2022	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	000	5	9/23/2022	COMPETING CONTINUATION	$613,235
														Subtotal = $613,235

Grand Total All Awards = $622,319

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Sub-cellular Targeting of Endothelial ROS in Myocardial Ischemia

Award Number: R56HL133624

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/10/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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