# Ceramide-Induced Destruction in Emphysema

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2023 · $681,732

## Abstract

Abstract
A hallmark of emphysema is the net loss of cells that form alveolar units required for gas exchange, due to
increased injury and impaired cell repair caused by inhalation of cigarette smoking (CS). Our proposal will
focus on how to enhance the survival and repair of lung microvascular endothelial cells, which are essential for
the maintenance of the alveolo-capillary membrane. To survive stress, injured cells engage a repair process,
autophagy, characterized by a sequence of steps (flux) devoted to the lysosomal degradation of damaged
proteins and organelles. Despite progress made in linking autophagy with COPD, little is known as to how CS
disrupts autophagic flux and approaches to restore its proper function are lacking. We propose to fill this
knowledge gap, by elucidating the regulation of lysosomal fitness and autophagic flux by sphingolipid
metabolites during homeostasis and CS exposure. We uncovered two sphingolipid rheostats (sphingosine/S1P
and ceramide/glucosylceramide) that control the autophagy flux, but are disturbed by CS. We hypothesize that
restoration of the sphingolipid rheostat is required to complete lysosomal autophagy and repair cigarette
smoke-induced lung microvascular endothelial cell injury and will alleviate emphysema. We will use
complementary approaches of human lung primary endothelial cells in 2D and 3D models of repair, including
co-cultured with alveolar type II epithelial cells, human precision cut lung slices, and mouse models of CS
exposure, to pursue three specific aims. Completion of these aims will fill important knowledge gaps in
emphysema pathogenesis, will mechanistically link targeted metabolomics with functional outcomes, and
provide potential new targets for treatment of emphysema.

## Key facts

- **NIH application ID:** 10615845
- **Project number:** 5R01HL077328-18
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Irina Petrache
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $681,732
- **Award type:** 5
- **Project period:** 2006-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10615845

## Citation

> US National Institutes of Health, RePORTER application 10615845, Ceramide-Induced Destruction in Emphysema (5R01HL077328-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10615845. Licensed CC0.

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