Investigating lipid-gene molecular profiles of septic ards
Active Project Grant Awarded Last action
- Award ID
- R21AI188477
- Recipient
-
Mayo Clinic Jacksonville (A Nonprofit Corporation) UEI GKPBCFV1QMM3
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $399,911
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 67% complete
- Originally
- Place of performance
- Jacksonville, FL 32224, USA
Award details come from USAspending.gov.
Description
- Abstract
- Sepsis is the most common cause (~75%) of acute respiratory distress syndrome (ards), a common condition with over 40% mortality. There are no effective pharmacotherapies for ards, likely due to patient heterogeneity. We have shown that HDL, which is usually anti-inflammatory/anti-oxidant, becomes dysfunctional (dyshdl) in sepsis, and becomes a negative regulator of inflammation, lipid oxidation, and chemotaxis. Dyshdl harbors an altered proteome and lipidome when compared to normal HDL and has not been studied in septic ards. We recently developed a panel of fifteen measurements including lipoproteins, inflammatory molecules, and clinical features and established two new sepsis phenotypes, hypo and normo. We applied our sepsis phenotyping pipeline (preliminary data) to septic ards patients and found that hypo septic ards patients had ~70% mortality, lower apoa-i, HDL-c, low density lipoprotein (LDL-c), worse endothelial dysfunction (icam-1), and higher organ failure severity when compared to normo septic ards patients (0% mortality). Moreover, hypo septic ards patient plasma contained significantly elevated lipoxygenase (LOX) pathway oxidized lipids (12- hete/15-hete) compared to normo septic ards. We also identified six upregulated lipid metabolism genes in peripheral blood leukocytes of hypo VS. Normo septic ards patients, critical for HDL/cholesterol biosynthesis, lipid/drug metabolism, and bacterial toxin clearance. Our central hypothesis is that unique phenotypes based on lipid-gene molecular patterns exist in septic ards that can be harnessed to reveal patient molecular heterogeneity. We further hypothesize that HDL metabolism and the LOX pathway play critical roles in septic ards, specifically in the hypo phenotype subset. Our MPI team with unique expertise will address major gaps in ards research by i) identifying novel septic ards phenotypes, II) systematically discovering repurposed drugs for septic ards treatment. Aim 1 will investigate hypo/normo phenotypes in septic ards patients, by measuring fifteen markers and dyshdl in 150 rose trial participant samples. We will perform targeted lipidomics to quantify the oxidized lipidome of LOX, COX, and P450 pathways and obtain untargeted transcriptomic signatures via whole blood rnaseq. We will localize expression patterns by cell type using single cell rnaseq in a small subset. Aim 2 will determine novel septic ards phenotypes utilizing lipidomic and transcriptomic profiles of septic ards patients. We will perform multi-omic, molecular phenotyping using an unsupervised machine learning approach to uncover novel lipidomic/transcriptomic phenotypes and link molecular phenotypes to potential drugs via drug-gene interactions.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $221,191 | |
| Amendment | -$245,503 | |
| Original award | $424,223 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| University Of California, LOS Angeles | $104,049 |
Quick answers
Who received award R21AI188477?
R21AI188477 was awarded to Mayo Clinic Jacksonville (A Nonprofit Corporation) by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on June 10, 2025.
How much is award R21AI188477 worth?
$399,911 has been obligated on R21AI188477.
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