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Variant Determinants of African American Limb Pathology in Peripheral Arterial Disease

Award Number: R01HL157659
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Variant Determinants of African American Limb Pathology in Peripheral Arterial Disease - Abstract Peripheral artery disease (PAD) is caused by atherosclerosis of the peripheral arteries, most commonly in the lower extremities, and affects 8-12 million individuals in the U.S. Cilastozol was the last drug approved to treat patients with PAD (1999) and twenty years of trials and pre-clinical testing have failed to advance therapeutics. PAD presents as either intermittent claudication (IC; pain with exertion that is relieved with rest) or critical limb ischemia (CLI; pain at rest with or without tissue necrosis or gangrene). Although less common than IC, CLI carries a substantially higher morbidity and mortality; CLI patients have a risk of major amputation or death that approaches 40% in one year. Differences in the clinical course of IC and CLI together with results of recent pre- clinical studies raise the intriguing possibility that IC and CLI represent distinct phenotypic manifestations of the same disease process. We propose an innovative idea; regenerating and functionally competent skeletal muscle supports ischemic neovascularization and vessel maturation - ultimately leading to the recovery of tissue blood flow and the prevention of tissue loss. Our proposal will directly test the ability of ischemic cells in the local limb microenvironment to alter tissue outcomes. We will interrogate the role of human BAG3 (Bcl-2 associated athanogene 3 - an evolutionarily conserved 575 amino acid protein) specifically in the limb muscle and endothelial cells of patients and mice. BAG3 is a multifunctional scaffolding protein and co-chaperone with pleiotropic effects in heart and skeletal muscle. It is a promising genetic candidate for therapeutic development in PAD for the following reasons: 1) mutations in BAG3 cause muscle myofibrillar myopathy and dilated cardiomyopathy in humans, 2) BAG3 variants exist in both African Americans with CLI (a demographic disproportionately affected by PAD - Preliminary Data) and cardiomyopathy, and 3) a murine coding variant in BAG3 regulates muscle regeneration, vascular density, and limb survival in a pre-clinical model of PAD (hindlimb ischemia-HLI). To that end, this proposal brings together clinical vascular surgeons, a skeletal muscle biologist who focuses on physiologic outcome measures, a biochemist and mitochondrial biologist who focuses on interrogating mitochondrial form and function in disease, a clinical cardiologist and researcher, and a translational scientist who studies skeletal muscle adaptability to injury and endothelial cell biology and has developed an unparalleled biobank of human PAD tissues. The central hypothesis of this proposal states that genetic variants in BAG3 result in myopathy and mitochondriopathy that disrupts communication between muscle and endothelial cells and results in a local muscle environment insufficient to support the vasculature. To that end, the Specific Aims are: 1) In PAD relevant models, determine the functional link between ischemic myopathy and angiogenesis. 2) Determine whether Cox6a2 expression is sufficient to rescue BAG3 variant induced myopathy in PAD conditions. 3) Establish whether BAG3 variants are a link between AA race and differences in CLI patient outcomes.


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	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	004	5	4/3/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$255,798
2025	2024	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	4	1/5/2025	NON-COMPETING CONTINUATION	-$386,505
2025	2024	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	003	4	4/3/2025	NON-COMPETING CONTINUATION	-$237,673
2025	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	001	5	1/6/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$386,505
2025	2023	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	002	3	4/3/2025	NON-COMPETING CONTINUATION	-$18,125
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $624,178 )
2024	2024	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	4	5/15/2024	NON-COMPETING CONTINUATION	$624,178
														Subtotal = $624,178

Issue Date FY: 2023 ( Subtotal = $645,013 )
2023	2023	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	3	3/14/2023	NON-COMPETING CONTINUATION	$645,013
														Subtotal = $645,013

Issue Date FY: 2022 ( Subtotal = $648,656 )
2022	2022	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	001	2	6/8/2022	NON-COMPETING CONTINUATION	$64,868
2022	2022	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	2	3/9/2022	NON-COMPETING CONTINUATION	$583,788
														Subtotal = $648,656

Issue Date FY: 2021 ( Subtotal = $673,663 )
2021	2021	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	001	1	7/2/2021	NEW	$67,369
2021	2021	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	1	3/19/2021	NEW	$606,294
														Subtotal = $673,663

Grand Total All Awards = $2,591,510

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Variant Determinants of African American Limb Pathology in Peripheral Arterial Disease

Award Number: R01HL157659

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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