# Necroinflammatory Cell Death in Sepsis

> **NIH NIH K23** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $194,940

## Abstract

PROJECT SUMMARY/ABSTRACT:
Sepsis is a deadly infection characterized by a dysregulated host immune response. Outcomes have failed to
improve despite decades of research. The immune response in sepsis is varied. Immunologic therapy has failed
in part due to the heterogeneity of the syndrome. Beyond the immunologically silent apoptosis,
necroinflammatory cell death, commonly necroptosis, is immunologically stimulating and can perpetuate
inflammation in sepsis. The initiation and coordination of necroinflammatory cell death is complex. TNF related
apoptosis inducing ligand (TRAIL) coordinates cellular processes associated with increased apoptosis and
necroinflammatory cell death. Receptor interacting serine/threonine kinase 3 (RIPK3) is essential to necroptotic
cell death. Our work has shown that RIPK3 is increased in septic patients in the intensive care unit in parallel
with increased organ dysfunction and is associated with poor outcomes. In the ICU, we have demonstrated that
lower TRAIL is associated with higher RIPK3 and increased organ dysfunction. In this project, we will examine
TRAIL and RIPK3 at three time points, in the emergency department and ICU. We hypothesize that
necroinflammatory cell death, characterized by high RIPK3 and low TRAIL will identify those who progress to
sepsis and septic shock and that there will be novel patterns of necroinflammatory cell death in patients at
increased risk of death with sepsis. AIM 1 will create a human cohort of patients at three critical time points
during an acute admission to the hospital. The first is soon after admission to the emergency department prior
to resuscitation and the administration of antimicrobial therapy. The follow up blood draws are obtained following
admission to the ward or ICU when organ dysfunction is established and therapy has been initiated. AIM 2 will
examine the relationship between TRAIL and RIPK3 and sepsis, septic shock and mortality through two
methodologies. The first will examine whether TRAIL and RIPK3 will increase our ability to diagnose sepsis when
combined with physiologic sepsis prediction tools in the emergency department. The second will evaluate the
effect of the follow up TRAIL and RIPK3 on outcomes, after modeling the effect of time dependent patient,
pathogen and treatment factors. For AIM 3, we will measure levels of a targeted mechanistic cell death panel
including, RIPK1, RIPK3, MLKL, along with key damage associated molecular patterns, mtDNA and HMGB1.
We will also evaluate a broader necroinflammatory biomarker panel in a proteomics platform. We will then
evaluate whether there are clusters of patients defined by relative biomarker levels together with physiologic
variables. We will examine if these patient clusters have differential outcomes. If the aims of this proposal are
achieved, we will have useful information concerning the role of necroinflammatory cell death in human sepsis
from multiple time points. Results from this study may offer in...

## Key facts

- **NIH application ID:** 10301742
- **Project number:** 1K23HL151876-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Edward James Schenck
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $194,940
- **Award type:** 1
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301742

## Citation

> US National Institutes of Health, RePORTER application 10301742, Necroinflammatory Cell Death in Sepsis (1K23HL151876-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10301742. Licensed CC0.

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