# Novel Approaches to Maintaining Organ Function in Sepsis

> **NIH NIH R35** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2022 · $508,781

## Abstract

PROJECT DESCRIPTION: Sepsis affects at least 1.7 million Americans annually, causing the death of
270,000 patients and including 30% of all hospital deaths. Unfortunately, there are no effective therapies for
patients with sepsis and septic shock. Excessive neutrophil activation is a critical determinant of inflammation
and tissue injury in sepsis. Therefore, targeting neutrophil activation, migration, and infiltration may be a
rational strategy to reduce sepsis morbidity and mortality. During the last funding period of this MIRA project,
we have made significant advances in the molecular mechanism of neutrophil and endothelial cell activation,
their interaction, and neutrophil infiltration in the lungs in sepsis. We previously reported extracellular cold-
inducible RNA-binding protein (eCIRP) as a new damage-associated molecular pattern molecule released in
sepsis to increase inflammation and cause acute lung injury. To continue our MIRA program, we aim to
explore the deep insights into neutrophils’ phenotypic and functional characteristics induced by eCIRP that
may aggravate organ injury in sepsis. We have discovered a previously unknown neutrophil population with
antigen-presenting, T-cell activating, and aged phenotypes, which we named antigen-presenting aged
neutrophils (APANs). APANs produce IL-12, which polarizes Th1 cells to generate interferon-, thereby
priming and inducing neutrophils to produce excessive neutrophil extracellular traps (NETs), causing further
tissue injury. Adoptive transfer of APANs aggravated sepsis and increased the mortality of septic animals,
suggesting that APANs play a critical role in sepsis pathobiology. However, APANs’ localization, induction,
and effector functions in sepsis remain unknown, as does their contribution to the immune and cognitive
dysfunction of sepsis survivors. We have recently predicted in silico and confirmed in vitro that our newly
discovered stable RNA mimic A12 binds to eCIRP with high affinity, decreasing eCIRPs affinity for its receptor,
inhibiting eCIRP’s ability to induce TNF release and to induce NETosis. Thus, A12 is a novel and potent
eCIRP inhibitor with the potential to attenuate the detrimental effects of eCIRP-induced APANs in sepsis. As
such, this renewal MIRA research program will address the following three key questions: 1) How does eCIRP
induce APANs, and what are their effector functions? 2) How do APANs aggravate sepsis? 3) Does targeting
eCIRP regulate APANs to mitigate sepsis? The proposed research will lead to a new direction for developing
innovative therapeutics to treat patients suffering from sepsis and septic shock by preventing or modulating the
novel hyperinflammatory neutrophil population of APANs.

## Key facts

- **NIH application ID:** 10405950
- **Project number:** 2R35GM118337-06
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** PING WANG
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $508,781
- **Award type:** 2
- **Project period:** 2016-06-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405950

## Citation

> US National Institutes of Health, RePORTER application 10405950, Novel Approaches to Maintaining Organ Function in Sepsis (2R35GM118337-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10405950. Licensed CC0.

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