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The Role of Plasmalogen Mitochondrial and Endothelial Antioxidant Properties in Sepsis

Award Number: F30HL170694
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 09/29/2027

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The Role of Plasmalogen Mitochondrial and Endothelial Antioxidant Properties in Sepsis - ABSTRACT Sepsis is triggered by bacterial, viral, or fungal infection, and it is characterized by multi-organ failure following an impaired host response. Sepsis ranks highly in both national in-hospital mortality and cost burden in comparison to all diseases. Sepsis treatment over the years has been limited to antibiotics, fluids, and organ support. New treatments are needed, which could potentially target sepsis cellular pathophysiology including excessive oxidative stress, inflammatory overactivation at the blood-endothelium interface, declines in mitochondrial health, and disordered lipid homeostasis. Plasmalogens are a unique class of phospholipids containing a characteristic vinyl ether bond at the sn-1 position, which links the glycerol backbone to the aliphatic chain. The vinyl ether bond is a target of reactive oxygen species (ROS), and thus plasmalogens are antioxidants. My recent studies have shown plasma plasmalogen levels are reduced in human sepsis, which likely reflects sepsis endothelial oxidative stress derived from redox enzymes and electron leakage from the mitochondrial electron transport chain (ETC). Mitochondrial damage by ROS impacts cellular respiration and lipid metabolism which is detrimental to overall cell health. This suggests a protective role for plasmalogens which reside in cell and organellar membranes, including the mitochondria. Lysoplasmalogen (lysoPls), a plasmalogen class lacking an acyl chain at the sn-2 position, is a useful plasmalogen precursor that displays more rapid cell uptake than plasmalogen and still contains the ROS-scavenging vinyl ether bond. Pilot data show that supplementation of lysoPls to human lung microvascular endothelial cells (HLMVECs) reduces cellular oxidative stress and maintains plasmalogen pools in the presence of pathogenic bacteria, and lysoPls supplementation protects HLMVEC barrier integrity in the presence lipopolysaccharide. Taken together, this suggests lysoPls have an ROS-scavenging role and provide critical endothelial protection during septic oxidative stress. Therefore, we hypothesize plasmalogen loss reflects injurious endothelial oxidative stress during sepsis, and plasmalogen replacement may limit oxidative stress, improving outcomes via mitochondrial and endothelial effects. Studies in Aim 1 will include: 1) examining human sepsis plasma plasmalogen levels as outcome predictors in collaboration with Dr. Nuala Meyer (University of Pennsylvania) and 2) testing plasmalogen replacement therapy in the mouse cecal ligation and puncture model of sepsis for protection against mortality and organ failure in collaboration with Dr. Richard Hotchkiss (Washington University). Physician-scientists Drs. Meyer and Hotchkiss will also serve as co-mentors for this training program. Studies in Aim 2 will test mechanisms that plasmalogen augmentation reduces inflammation and oxidative stress in the endothelium, improving endothelial function. Overall, these studies open new research avenues to distinguish sepsis targets and therapeutics and to ultimately improve sepsis patient outcomes, especially given the rise of antibiotic resistance in recent decades.


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 = $54,538 )
2025	2025	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	3	8/18/2025	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	2	8/23/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	1	8/15/2023	NEW	$52,694
														Subtotal = $52,694

Grand Total All Awards = $161,206

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The Role of Plasmalogen Mitochondrial and Endothelial Antioxidant Properties in Sepsis

Award Number: F30HL170694

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 09/29/2027

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