# The Role of PPARa in Cardiac Dysfunction in Sepsis

> **NIH NIH K08** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $162,000

## Abstract

Project Summary/Abstract
Sepsis is a severe condition that often results in life-threatening multiorgan dysfunction. This proposal
describes a 5-year research and training program that will permit Dr. Stephen Standage to develop as an
independent investigator conducting clinically relevant, basic and translational research in sepsis
pathogenesis. Having completed fellowship training in pediatric critical care medicine and building on a
background of basic research training in sepsis immunology, the applicant seeks to develop new knowledge
and skills to investigate how regulation of metabolic pathways influences organ dysfunction in sepsis with an
objective to identify key mechanisms and therapeutic interventions that may improve patient outcomes.
This research project specifically focuses on elucidating how PPARα influences cardiac energy production and
heart function in sepsis. PPARα is a nuclear hormone receptor transcription factor that regulates many
inflammatory and metabolic processes. Previous research has demonstrated that children with septic shock
have significant downregulation of PPARα in peripheral blood leukocytes. The applicant's preliminary studies
demonstrated that mice lacking PPARα (Ppara-/-) have much higher mortality in experimental sepsis, but
reconstitution with bone marrow from wild type mice did not rescue the mortality phenotype, indicating a critical
role for tissue PPARα in regulating organ injury and mortality in sepsis. Septic Ppara-/- mice have elevated
plasma and tissue markers of severe cardiac injury and show decreased heart function compared to wild type
mice, findings that are associated with lower fatty acid oxidation in the Ppara-/- group. Collectively, these data
support the overall hypothesis that PPARα preserves cardiac function in sepsis by activating fatty acid
oxidation and that augmenting cardiac PPARα signaling will improve survival. The specific aims of the
proposed investigations are to: 1) Define the role of PPARα expression in heart function and survival in sepsis
using a novel transgenic, cardiac-specific PPARα knock-out mouse and a mouse strain that over-expresses
PPARα in the heart; 2) Identify the metabolic pathways that influence PPARα dependent cardiac function in the
heart by measuring cardiac ATP production and substrate utilization, tissue gene expression and metabolite
levels, and by evaluating mitochondrial structure and function; and 3) Determine whether pharmacologic
PPARα activation ameliorates septic cardiac dysfunction and improves survival.
This work is significant and has high translational potential because PPARα signaling is a targetable
mechanism with FDA approved agonists already on the market. The hypotheses evaluated here challenge the
prevailing paradigm that sepsis morbidity and mortality result from immune dysregulation and findings will have
the potential to reframe the approach to treating this significant public health problem.

## Key facts

- **NIH application ID:** 9986871
- **Project number:** 5K08HL133377-05
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Stephen Wade Standage
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,000
- **Award type:** 5
- **Project period:** 2017-08-10 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986871

## Citation

> US National Institutes of Health, RePORTER application 9986871, The Role of PPARa in Cardiac Dysfunction in Sepsis (5K08HL133377-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9986871. Licensed CC0.

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