# Epigenetic mechanisms of immune reprogramming in murine sepsis survivors

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $54,522

## Abstract

Project Summary/Abstract:
This proposal describes a two-year training plan designed to provide the PI with the technical skills, scientific
models and knowledge to facilitate earning a K08 award on epigenetic mechanisms of the altered host
response to lung injury in sepsis survival.
Applicant: Dr. Denstaedt holds an MD degree and has completed specialty training in Internal Medicine and
Pulmonary and Critical Care Medicine. He has previous experience several basic science research labs. He
has had an intensive research experience during the last 18 months of Pulmonary and Critical Care fellowship
and is currently a T32 post-doctoral research trainee. The training outlined is designed to develop his skills in
assessments of lung injury, model development, epigenetics and bioinformatics. The lab science, mentorship
team, and didactics were selected to specifically advance his training toward becoming and independent
physician-scientist.
Research plan: Despite substantial advances in medical care, recovery from sepsis is associated with
increased risk for long-term organ injury and death. Nearly 1 in 10 patients with sepsis will be re-hospitalized
within 90-days with respiratory conditions including pneumonia, respiratory failure and aspiration pneumonitis.
Other than supportive care and rehabilitation, there are no targeted therapies to prevent lung-related
complications in sepsis survivors. Interestingly, survivors of murine sepsis have enhanced (primed) innate
immune responses suggesting an activated immune program is experienced in sepsis survival. Innate immune
priming has been associated with persistent elevations of the danger signal protein S100A8/A9. Given that
sepsis survival is associated with significant long term morbidity and mortality, the central hypothesis of this
proposal is that primed innate immune responses, mediated by persistent danger signal proteins, are
associated with a predisposition to secondary lung injury. This project focuses on examining epigenetic
mechanisms of persistent immune priming through modeling of secondary lung injury to mimic a clinically
relevant reason for re-admission in the post-septic patient. In Aim 1, a murine model of polymicrobial sepsis
survival will be used to evaluate the effect of sepsis on secondary inflammatory lung injury. Lung
macrophage/monocytes will be isolated by flow cytometry and cell sorting, and stimulated ex vivo to evaluate
for a primed phenotype two weeks after sepsis. Chromatin immunoprecipitation (ChIP)-seq and assessment of
chromatin modifying enzyme expression via quantitative PCR will be performed to assess dynamic changes in
the epigenome and its machinery. In Aim 2, an in vitro model of S100A8/A9 mediated priming of wild-type bone
marrow derived macrophage (BMDM) will be developed with subsequent ChIP and chromatin modifying
enzyme measurement as in Aim 1. These experiments will be compared in BMDM from post-septic wild-type
and S100A9-/- mice.

## Key facts

- **NIH application ID:** 10017703
- **Project number:** 5F32HL149182-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Scott John Denstaedt
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $54,522
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017703

## Citation

> US National Institutes of Health, RePORTER application 10017703, Epigenetic mechanisms of immune reprogramming in murine sepsis survivors (5F32HL149182-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10017703. Licensed CC0.

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