# Mitochondrial Determinants of Cognitive Outcomes in ARDS and Sepsis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $387,695

## Abstract

PROJECT SUMMARY
Acute respiratory distress syndrome (ARDS) and sepsis claim the lives of hundreds of thousands of patients
worldwide each year. Improved care has reduced mortality due to ARDS and sepsis, but up to 80% of
ARDS/sepsis patients develop acute brain dysfunction in the form of delirium, a major complication associated
with prolonged ICU and hospital stays and increased mortality. Even when delirium symptoms resolve, many
patients never regain normal cognition, instead struggling with an acquired, dementia-like, long-term cognitive
impairment. With a limited understanding of the pathophysiology of brain dysfunction due to ARDS and sepsis,
there are currently no cognition-preserving therapies for ARDS/sepsis patients. Animal and human studies
have shown that the inflammatory response of ARDS/sepsis imposes a stress on cells and tissues
characterized by increased production of reactive oxygen species (ROS), decreased oxygen delivery, impaired
oxygen consumption, metabolic reprogramming increasing lactate production, and dysregulation of cell
proliferation/apoptosis. This stress response is mediated by mitochondria, which produce ROS, regulate
oxygen and nutrient metabolism, and control initiation of apoptosis. Mitochondrial dysfunction has been
implicated in sepsis-induced injury of lung (i.e., ARDS) as well as heart, muscle, and kidneys, but the most
metabolically vulnerable organ—the brain—remains poorly studied in this context. We hypothesize that
mitochondrial function and key variables that impact it, e.g., mitochondrial DNA (mtDNA) haplogroup, are major
determinants of delirium and long-term cognitive impairment due to ARDS and sepsis. To test this central
hypothesis, we will complete the following Aims: (1) Test the hypotheses that specific mtDNA haplogroups are
independently associated with delirium and long-term cognitive impairment due to ARDS and sepsis; (2) test
the hypotheses that alterations in mitochondrial oxidative metabolism, systemic oxidant injury, and
mitochondrial injury are predicted by mtDNA haplogroup and are independently associated with delirium and
long-term cognitive impairment due to ARDS and sepsis; and (3) test the hypotheses that alterations in
multiple specific metabolic pathways affected by mitochondrial dysfunction in the brain are independently
associated with delirium and long-term cognitive impairment due to ARDS and sepsis. We will complete Aim 1
using Vanderbilt’s BioVU DNA Databank and electronic medical record as well as data and DNA collected
during the NIH-funded BRAIN-ICU study, Aim 2 using data and specimens collected in the BRAIN-ICU study,
and Aim 3 using data and specimens collected from a prospective cohort of patients with ARDS and/or sepsis.
By elucidating the pathophysiology of ARDS/sepsis-associated brain dysfunction, this work will in due course
lead to strategies that preserve cognitive function for millions who will suffer from ARDS or sepsis in the future.

## Key facts

- **NIH application ID:** 10114314
- **Project number:** 5R01HL135144-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Timothy D Girard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $387,695
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114314

## Citation

> US National Institutes of Health, RePORTER application 10114314, Mitochondrial Determinants of Cognitive Outcomes in ARDS and Sepsis (5R01HL135144-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10114314. Licensed CC0.

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