# Mitochondrial Dysfunction in the Endothelium as a Mediator of Inflammatory Injury

> **NIH NIH P01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $428,492

## Abstract

ABSTRACT
Studies have shown that the endothelium plays a critical role in host defense by regulating the influx and phenotype
of immune cells. Project 3 focuses on delineating the role of mitochondrial dysfunction and mitophagy in endothelial
cells in regulating lung vascular homeostasis and host-defense during injury. The proposed studies will identify
mechanisms of mitochondrial injury in ECs as well as how adaptive mitophagy activates compensatory mitochondrial
biogenesis. Project 3 will also examine how mitophagy and the release of mitochondrial peptides impact neutrophils
during inflammatory lung injury. The fundamental questions that will be addressed by this proposal include: What
are the mechanisms of TNFα induced mitochondrial injury and mitophagy? Can we use biosensors for mitochondria
in vitro and in vivo to define key phases of mitophagy and compensatory mitochondrial biogenesis? How does
endothelial mitophagy affect restoration of endothelial metabolism and endothelial regeneration? How does
endothelial mitophagy impact neutrophil signaling, inflammatory injury and host defense. Project 3 will test the
overall hypothesis that lung endothelial mitophagy is a central regulator of endothelial homeostasis and the innate
immune response. This will be addressed in two Aims. Aim 1: Determine the role of endothelial mitophagy and
compensatory mitochondrial biogenesis to restore endothelial regeneration and homeostasis during
inflammatory lung injury. Here we will test the hypothesis that inflammation induces mitochondrial injury and
adaptive mitophagy in the lung endothelium to orchestrate endothelial regeneration and homeostasis. Furthermore,
we posit that the central mechanism of restoring homeostasis is through the compensatory mitochondrial biogenesis.
We use intravital two photon imaging of endothelial mitophagy (with Core D) and perform in vivo studies using EC-
specific genetic deletion of the mitophagy mediator PINK1, the mitochondrial biogenesis transcription factors PGC1α
and TFAM, and the mitochondrial phosphatase PGAM5 (which transfers post-mitophagy signaling to the nucleus)
with mechanistically driven in vitro studies in human lung ECs. These studies will be coupled to analysis of EC
metabolism, mitochondrial biogenesis, and EC regeneration. Aim 2: Determine the role of endothelial mitophagy
in activating the lung host-defense function during inflammatory injury. Here we will test the hypothesis that
EC-mitophagy increases transendothelial neutrophil influx and thereby bacterial killing through secretion of
formylated peptides and activation of formyl peptide receptors. We will use genetic models of EC-specific PINK1
deletion in distinct models of inflammatory lung injury (LPS and Pseudomonas pneumonia) and analyze EC
epigenetic and transcriptomic regulation (with Core B) wrought by mitophagy and address how these contribute to
host-defense function of EC and neutrophils downstream of EC PINK1. We will also assess how EC-PINK1 ...

## Key facts

- **NIH application ID:** 10706520
- **Project number:** 5P01HL160469-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jalees Rehman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $428,492
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10706520

## Citation

> US National Institutes of Health, RePORTER application 10706520, Mitochondrial Dysfunction in the Endothelium as a Mediator of Inflammatory Injury (5P01HL160469-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10706520. Licensed CC0.

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