# Purinergic signaling in trauma and sepsis

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $332,100

## Abstract

PROJECT SUMMARY
Sepsis is a clinical syndrome, which complicates severe infection. It remains the leading cause of morbidity
and mortality in critically ill patients. Current concepts suggest that organ failure and mortality in sepsis are
caused by inappropriate regulation of host defenses and the immune system. This manifests as an inability to
control bacterial growth and dissemination, and excessive inflammation, processes that are interrelated and
are due, in a large part, to macrophage dysfunction. Danger-associated molecular patterns (DAMP)s comprise
a diverse group of molecules that accumulate in the extracellular space in response to bacteria-mediated
tissue destruction, trauma, and burns, all of which are associated with sepsis. ATP is a major DAMP, which is
released from the intracellular into the extracellular space through connexins and pannexins during
inflammation, infection, shock, and sepsis. Extracellular ATP binds to and signals through P2 receptors to
modulate immune function. Our preliminary data with mice deficient in P2 receptors, as well as
pharmacological receptor and channel ligands establish that ATP release through connexin/pannexin channels
and subsequent P2 receptor activation are crucial for the control of mortality, bacterial killing and dissemination
and inflammation following cecal ligation and puncture, a clinically relevant model of polymicrobial sepsis.
Mechanistically, we show that ATP and one of the P2 receptors, the P2X4 receptor, protects against sepsis by
directly increasing the killing of bacteria by macrophages. Based on these data, we hypothesize that ATP
governs the host's response to sepsis by signaling through P2 receptors on macrophages. To address this
hypothesis, we will pursue the following Specific Aims: 1. Identify the mechanisms that support ATP release
during sepsis. 2. Dissect the mechanisms by which P2X4 receptor stimulation augments the killing of sepsis-
causing extracellular bacteria by macrophages. 3. Identify the monocyte/macrophage populations that are
targets of P2 receptor-mediated immune regulation in sepsis. The overarching goal here is to delineate the role
of P2 receptors in protecting against severe infection and to determine whether these receptors can be
specifically targeted to manage patients with sepsis.

## Key facts

- **NIH application ID:** 9991857
- **Project number:** 5R01GM066189-17
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** George HASKO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $332,100
- **Award type:** 5
- **Project period:** 2002-07-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991857

## Citation

> US National Institutes of Health, RePORTER application 9991857, Purinergic signaling in trauma and sepsis (5R01GM066189-17). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9991857. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*