# Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $570,731

## Abstract

SUMMARY:
Sepsis is a significant cause of morbidity and mortality. Severe sepsis complicated with multiple organ injury and
acute lung injury (ALI)-induced respiratory failure frequently serves as a direct reason of death. During sepsis,
unrestrained stimulation of leukocytes and structural cells can induce Systemic Inflammatory Response
Syndrome (SIRS) resulting in tissue injury and susceptibility to nosocomial infection. Unfortunately, as no
effective medicine is available to treat the developing SIRS/organ injury in these individuals, there is a strong
need to further dissect the complex events that lead to the initiation and progression of SIRS. The long-term goal
of this project is to identify endogenous inhibitors of phagocyte function that could decrease different arms of the
inflammatory response while restoring antimicrobial effector functions. This renewal is built upon published and
preliminary data generated while investigating the role of the phosphatase and tensin homolog PTEN in
microRNA-mediated MyD88 degradation and the generation of SIRS during sepsis. We found that PTEN
deficiency enhances mortality in septic mice; that miR21 (a microRNA that targets PTEN) is a homeostatic
regulator of macrophage inflammatory response and that preventing excessive glycolysis decreases SIRS
development, ALI formation and improves animal survival. Our preliminary data suggest that in addition to
controlling transcriptional programs, PTEN also directly inhibits the inflammasome (intracellular inflammatory
platforms)-dependent release of potent inflammatory mediators. PTEN also stimulates fatty acid oxidation (FAO),
which inhibits inflammation. Furthermore, we also found that miR21 inhibits the expression of genes involved in
FAO, which correlates with decreased animal survival, increased lung inflammation and mortality. From these
findings, we formulated our central hypothesis that during sepsis, myeloid-specific signaling along the
miR21/PTEN/FAO axis becomes dysregulated and drives lung injury and lethality during sepsis. This hypothesis
will be examined by testing the 1) role of PTEN in inflammasome activation in phagocytes in sepsis and 2)
Determine the role of the miR21/PTEN axis in lung injury and mortality during sepsis. We will employ a series of
state-of-the-art techniques, along with epistatic and gain of function approaches to unveil new signaling programs
that ultimately might influence ALI and mortality during systemic infections. The combination of the PI’s
experience in sepsis, lung immunology and inflammation, the assembled team of collaborators, and the
environment at Vanderbilt University Medical Center ensure that this work will be accomplished. The
identification of specific components and their modes of action in maintenance of sepsis may identify targets for
therapeutic intervention resulting in improved immune responsiveness in settings of host vulnerability, and may
suggest strategies to dampen the immune response in settin...

## Key facts

- **NIH application ID:** 10201714
- **Project number:** 5R01HL124159-08
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** C. Henrique Serezani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $570,731
- **Award type:** 5
- **Project period:** 2014-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201714

## Citation

> US National Institutes of Health, RePORTER application 10201714, Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis (5R01HL124159-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201714. Licensed CC0.

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