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Cell-Free Hemoglobin Induces Endothelial Mitochondrial Oxidative Damage Causing Extracellular DNA Release

Award Number: F31HL167471
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Cell-Free Hemoglobin Induces Endothelial Mitochondrial Oxidative Damage Causing Extracellular DNA Release - PROJECT ABSTRACT Sepsis is a critical problem around the world causing 20% of all global deaths. The lack of highly effective therapeutics leaves critically ill patients with systemic organ dysfunction often caused damage the vascular endothelium. Our lab has shown that one of the drivers of vascular dysfunction in sepsis is circulating oxidized cell-free hemoglobin (CFH). During septic conditions, red blood cells become increasingly fragile leading to lysis and release of CFH into the vascular circulation allowing for oxidation from ferrous (2+) and oxidized ferric (3+, methemoglobin) forms. Data from our lab demonstrates that only the oxidized 3+ form of CFH induces microvascular barrier dysfunction. However, the intracellular mechanisms underpinning this dysfunction are not well understood. My preliminary studies suggest that oxidized CFH causes mitochondrial dysfunction such as increased superoxide production and loss of total mitochondria. In parallel to circulating CFH being increased in septic patients, there is increased circulating extracellular mitochondrial DNA (mtDNA) during sepsis. Importantly, the mechanism underlying release of mtDNA during sepsis remains a key knowledge gap. In addition, it is unknown whether the mtDNA is released as freely soluble molecules or if it is inside extracellular vesicles (EVs). Understanding if mtDNA is contained inside EVs could inform potential effects, distribution, and stability of the circulating mtDNA. In this project, I will test the hypothesis that CFH-induced oxidative damage causes mtDNA release from the vascular endothelium leading to downstream loss of macrovascular barrier integrity. The first aim of this project focuses on identifying the mechanisms behind CFH-induced oxidative damage and its role in mtDNA release from the pulmonary microvascular endothelium. We will evaluate the impact of CFH on mitochondrial oxidative damage and permeability pore activation. In addition, we will quantify whether the mtDNA is freely soluble or contained inside EVs, and if antioxidants block this secretion. The second aim of the project will determine the effect of mtDNA on endothelial barrier function. We will also use platelet poor plasma from a highly characterized prospective cohort of sepsis patients to quantify circulating mtDNA and correlate levels with mortality, ARDS development, and markers of endothelial damage. At the conclusion of this study, we will have uncovered a novel molecular mechanism of CFH induced vascular dysfunction, and characterized both the effects of mtDNA and how it is released from endothelial cells. This proposed project will provide multidisciplinary experience and growth to establish the foundation for a successful career as a mechanistic and translational scientist.


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 = -$522 )
2026	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	3	6/23/2026	NON-COMPETING CONTINUATION	-$522
														Subtotal = -$522

Issue Date FY: 2025 ( Subtotal = $27,382 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	3	11/20/2024	NON-COMPETING CONTINUATION	$26,959
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	001	3	9/16/2025	NON-COMPETING CONTINUATION	$423
														Subtotal = $27,382

Issue Date FY: 2024 ( Subtotal = $34,243 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	001	2	9/13/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	11/23/2023	NON-COMPETING CONTINUATION	$32,963
														Subtotal = $34,243

Issue Date FY: 2023 ( Subtotal = $32,945 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	001	1	3/11/2023	NEW	$942
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	002	1	3/11/2023	NEW	$0
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	11/30/2022	NEW	$32,003
														Subtotal = $32,945

Grand Total All Awards = $94,048

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Cell-Free Hemoglobin Induces Endothelial Mitochondrial Oxidative Damage Causing Extracellular DNA Release

Award Number: F31HL167471

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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