# Pathological Myeloid Activation After Sepsis and Trauma

> **NIH NIH R35** · UNIVERSITY OF FLORIDA · 2023 · $381,250

## Abstract

ABSTRACT
Sepsis and severe trauma are linked with challenging clinical trajectories as well as dismal long-term outcomes
following hospital discharge. In surgical intensive care units (SICUs), an alarming percentage of sepsis and
trauma patients can develop chronic critical illness (CCI; prolonged acute-care and chronic-care hospitalization
with unresolved organ dysfunction). CCI frequently manifests as a persistent inflammation, immunosuppression
and catabolism syndrome (PICS). SICU survivors suffering from PICS have repeat infections, poor cognitive
performance, physical dysfunction and self-reported poor quality of life. These conditions, at least in part, are
due to an unresolving pathologic myelopoiesis and ensuing prevalence of distinct myeloid-derived suppressor
cells (MDSCs). The principal investigator (PI) and his collaborators have demonstrated significant productivity
over the last decade, especially in the last five years, in this research field. The PI’s laboratory has conducted
human and murine research to establish that enhanced production of these distinct MDSCs is associated with
poor outcomes in sepsis and trauma. The laboratory has also discovered key distinctions in these MDSCs’
accompanying pathologic myeloid activation; for example, they are potently immunosuppressive towards
macrophages, CD4+ and CD8+ T cells; while concurrently, they produce inflammatory cytokines, reactive nitric
oxide (NO), oxidation and peroxidation products that damage parenchymal cells and promote inflammation. We
hypothesize that microRNAs and immunometabolism affect each other in relation to the development and
suppressive activity of these MDSCs. Our overarching goal for this application is to build upon this foundation
and expand our understanding of the patient immune response to trauma and sepsis, including rationally
designing prophylactic and/or therapeutic interventions aimed at treating or preventing grim clinical trajectories
and long-term outcomes following sepsis or trauma. This includes identifying sepsis and trauma patient
populations at risk of dying or having long-term morbidity. We intend: (1) to examine specific mechanisms,
including epigenetic and metabolic changes, to MDSC pathophysiology that engender or maintain pathologic
myeloid activation. MDSC and hematopoietic stem and progenitor cell (HSPC) studies will be both descriptive
and interventional (ex vivo). For example, MDSCs will undergo phenotypic analysis as well as CITE-seq using
10X Genomics, and HSPCs isolated from bone marrow and blood will undergo phenotypic and functional
analysis. With these studies, we will (2) explore the unique biology of pathologic myeloid cell activation in different
cohorts of sepsis and trauma patients (such as different patient age and sex groups); and (3) consider possible
immunomodulative therapies that affect MDSCs and/or pathologic myeloid activation to mitigate or prevent
CCI/PICS. This MIRA would support and enable the PI and his laborat...

## Key facts

- **NIH application ID:** 10593977
- **Project number:** 5R35GM140806-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Philip A Efron
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593977

## Citation

> US National Institutes of Health, RePORTER application 10593977, Pathological Myeloid Activation After Sepsis and Trauma (5R35GM140806-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10593977. Licensed CC0.

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