# Operationalizing the RAGE Axis in Acute Respiratory Distress Syndrome

> **NIH NIH K01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $161,999

## Abstract

Abstract
Acute respiratory distress syndrome (ARDS) is a common and fatal clinical condition characterized by
inflammatory lung injury, airspace edema, and hypoxemia. The syndrome occurs in an estimated 190,000
patients annually and complicates approximately 24% of admissions to the intensive care unit for mechanical
ventilation. The estimated mortality of ARDS is between 35-40%, yet there are currently no effective
pharmacological interventions targeted at the disease pathophysiology. Development of disease-specific therapy
has been limited by the heterogeneity of ARDS. The identification of biologically-defined subgroups in ARDS
may facilitate a precision medicine approach for novel ARDS therapy. The receptor for advanced glycation
endproducts (RAGE) pathway is a promising target for ARDS therapies. RAGE is a multiligand pattern
recognition receptor on alveolar epithelial cells that amplifies immune and inflammatory responses. RAGE
ligands such as HMGB1, AGE, S100A12, and other damage-associated molecular patterns provoke
inflammatory signal propagation via RAGE. The soluble form of RAGE (sRAGE) has been implicated in impaired
alveolar fluid clearance and is a leading biomarker for ARDS risk and mortality in human studies. RAGE
modulating therapies have been shown to improve acute lung injury in animal models, but the translation to
human ARDS is challenging. We applied Mendelian randomization (MR), a genetic causal inference method, to
plasma sRAGE to assess the association with ARDS risk. Our MR method identified a potential causal
relationship between plasma sRAGE and ARDS risk. However, it is unknown whether plasma sRAGE directly,
or indirectly via other pathways that shape plasma sRAGE levels, drive the observed effect. Our global
hypothesis is that the RAGE pathway causally confers risk for sepsis-associated ARDS, and a RAGE molecular
signature can define a sepsis subgroup at high risk for ARDS. This application will use a cohort of septic subjects
to characterize the causal contributions of RAGE-cleaving matrix metalloproteinases (MMPs) and RAGE ligands
to ARDS risk, and develop predictive utility thresholds to enrich future clinical trials with patients likely to benefit
from anti-RAGE axis therapies. The long-term goal of this research is to develop a precision medicine approach
to ARDS therapy based on the RAGE axis. Aim 1 examines the role of RAGE-cleaving MMPs in conferring risk
for ARDS using MR and mediation analysis. Aim 2 evaluates the causal contributions of the major RAGE ligands
to ARDS risk using MR. In Aim 3, we will develop and validate a predictive model that employs RAGE-axis-
based thresholds to identify a high-risk population for ARDS in two independent cohorts of critically ill patients
with sepsis. The predictive model from Aim 3 may be used for population enrichment in future clinical trials of
anti-RAGE axis therapies. The specific aims, training objectives, and structured mentorship in this proposal will
bestow th...

## Key facts

- **NIH application ID:** 10119324
- **Project number:** 5K01HL149851-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Tiffanie Kae Jones
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $161,999
- **Award type:** 5
- **Project period:** 2020-03-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119324

## Citation

> US National Institutes of Health, RePORTER application 10119324, Operationalizing the RAGE Axis in Acute Respiratory Distress Syndrome (5K01HL149851-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10119324. Licensed CC0.

---

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