# NIH grant: Targeting Plasmalogen Dysregulation for Sepsis Prognostication and Treatment (1R01HL186403-01A1) — retained record

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NIH grant 1R01HL186403-01A1: Targeting Plasmalogen Dysregulation for Sepsis Prognostication and Treatment
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: DAVID A. FORD. Award: $617477.
Start: 2026-07-16T00:00:00.
Sepsis is a major cause of morbidity and mortality in both adults and children with ~1 million cases per year in
the United States. Sepsis pathophysiology encompasses complex interactions involving microbes, blood cells
and the endothelial barrier of the microcirculation that can progress to vascular collapse and organ failure. The
endothelium is subjected to oxidative stress during sepsis, which contributes to microcirculatory dysfunction.
Plasmalogens are a major subclass of phospholipids present in the endothelium which provide protection against
oxidative stress. Endothelial plasmalogen levels are maintained by both regulated biosynthetic pathways and
uptake from the plasma. Pilot studies in septic humans show: 1) low circulating levels of plasmalogens including
plasmenylethanolamine, plasmenylcholine, lysoplasmenylethanolamine (pLPE) and lysoplasmenylcholine
(pLPC) at ICU admission (day 0) and 2) low plasma levels of specific plasmalogen molecular species associate
with mortality. Also, our previous studies with the cecal slurry sepsis model revealed both plasmalogen dysreg-
ulation and multi-organ injury accompanied by barrier disruption (2, 3). We hypothesize plasma plasmalogen
dysregulation during sepsis reflects uptake of plasma plasmalogens by endothelium to compensate for oxidative
stress-caused loss of plasmalogens in the endothelium. Sepsis dysregulation of plasma pLPE and pLPC may
be critical since these amphipathic species readily traverse endothelial cell membranes and may be essential in
replenishing protective endothelial cell plasmalogen pools. Supporting preliminary data show: 1) pLPC protects
endothelial cells from plasmalogen dysregulation and oxidant stress during bacterial challenge and 2) pLPE
reduces pro-inflammatory prostaglandin E2 production during endotoxin challenge. Overall, the proposed stud-
ies will identify mechanisms responsible for plasmalogen dysregulation, provide evidence that plasmal-
ogen dysregulation represents a therapeutic target for sepsis and demonstrate plasma plasmalogen
levels are prognostic indicators of sepsis outcomes. There are three aims: Aim 1 will elucidate mecha-
nisms of plasmalogen dysregulation in an infectious sepsis model. Stable isotope labeling techniques will be
used to determine dysregulated plasmalogen biosynthesis. Plasmalogen replacement therapy (PRT) will be ex-
amined for protection against sepsis elicited multi-organ failure, inflammasome activation and immunosuppres-
sion. Aim 2 will test mechanisms responsible for plasmalogen dysregulation during bacterial oxidative stress in
primary human cells. Aim 3 will test the hypothesis that plasma plasmalogens at ICU admission associate with
organ failures and death in sepsis. Overall, plasmalogen dysregulation will be examined in human and rat sepsis
as well as human cells subjected to oxidative stress caused by bacteria and endotoxins. PRT will be tested as a
novel treatment to reduce sepsis multi-organ failure and immunosuppression by our multi-disciplinary group at
Saint Louis University. Studies will also meld the expertise of the Ford lab with Drs. Meyer and Shashaty at Penn
to examine plasma plasmalogens as prognostic indicators of sepsis caused multi-organ failure and mortality.
```



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