# Exosomal Gasdermin D Mediated Lung to Brain Crosswalk in Preterm Brain Injury

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $457,511

## Abstract

PROJECT SUMMARY
Bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development is the
most common morbidity complicating preterm birth, and a predictor of poor neurodevelopmental outcomes.
Currently it is unclear to what extent lung injury contributes to neurodevelopmental impairment (NDI) in these
preterm infants. Based on our preliminary data which demonstrate that circulating exosomes derived from
preterm infants who develop severe BPD induce neural stem cell (NSC) death in vitro, the major goal of this
proposal is to determine the molecular mechanisms by which these circulating exosomes mediate lung to brain
crosstalk and their contribution to brain injury and NDI. Understanding these mechanisms is fundamental to
public health as more preterm infants are surviving, yet there remains no effective therapy for either BPD or its
associated NDI. Pyroptosis is a newly described form of inflammatory cell death that is solely regulated by
gasdermin D (GSDMD), an inflammasome-activated membrane “pore-forming” protein. Exosomes are nano-
sized extracellular vesicles that play a key role in inter-organ communications. We recently demonstrated that
preterm infants who develop severe BPD have increased expression of GSDMD and surfactant protein C (SPC),
a marker of alveolar type II epithelial cells (AEC), in their circulating exosomes at 1 week of age. In preclinical
studies with an experimental model of BPD, similar GSDMD-containing exosomes were isolated from the serum
of newborn rats exposed to hyperoxia. Importantly, adoptive transfer of these exosomes into the circulation of
normal newborn rats impaired brain development. These findings lead us to propose a novel model that links
BPD, exosomal GSDMD and brain injury. The central hypothesis of this model is that GSDMD-containing
exosomes are released from AEC into the circulation during the evolving stage of BPD, and neuronal uptake of
these exosomes results in neural cell pyroptosis and NDI. This hypothesis will be tested through three aims: Aim
1. To characterize the relationship between GSDMD expression profiles in AEC-derived circulating exosomes
and the severity of BPD in preterm infants. Aim 2. To determine the mechanistic functions of circulating
exosomes from preterm infants in inducing brain injury and NDI. Aim 3. To elucidate the molecular mechanisms
by which hyperoxia stimulates AEC to release GSDMD+ exosomes that induce brain injury and NDI. These
studies will delineate a novel exosomal GSDMD-mediated lung to brain crosstalk that is critical in the
pathogenesis of brain injury and NDI in premature infants. Completion of this project will provide a strong
foundation to further explore therapeutic interventions that target exosomal GSDMD to improve long-term
respiratory and neurodevelopment outcomes in these infants. This proposal is aligned with the overarching goal
of the NICHD and NHLBI that is to improve children’s health through cutting edge researc...

## Key facts

- **NIH application ID:** 10653147
- **Project number:** 5R01HL156803-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** SHU WU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $457,511
- **Award type:** 5
- **Project period:** 2020-08-05 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10653147

## Citation

> US National Institutes of Health, RePORTER application 10653147, Exosomal Gasdermin D Mediated Lung to Brain Crosswalk in Preterm Brain Injury (5R01HL156803-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10653147. Licensed CC0.

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