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

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $105,528

## Abstract

ABSTRACT
I sincerely thank NIH for the opportunity to apply for this Administrative Supplement for Continuity of
Biomedical and Behavioral Research Among First-Time Recipients of NIH Research Project Grant
Awards Facing Critical Life Events (NOT-OD-23-032). My research is currently supported by an R01 grant
from NHLBI (1RO1HL156803-01A1), which I obtained in August 2020. The major goal of this grant is to
determine the mechanisms by which circulating extracellular vesicles (EVs) mediate lung-to-brain crosstalk and
their contribution to brain injury and neurodevelopmental impairment (NDI) in preterm infants. EVs play a crucial
role in inter-organ communications. 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. Activation
of GSDMD depends on the activation of caspase-1, which is achieved by assembling an inflammasome complex
with the apoptosis-associated speck-like protein containing a card (ASC). Our studies demonstrated that preterm
infants who develop bronchopulmonary dysplasia (BPD), a chronic lung disease, have increased expression of
ASC and GSDMD in their circulating EVs at 1 week of age. Importantly, the adoptive transfer of these EVs into
the circulation of normal newborn mice induced lung inflammation and impaired brain development. These
findings led us to propose a novel model that links BPD, EV-ASC, EV-GSDMD, and brain injury. The central
hypothesis of this model is that ASC-containing and GSDMD-containing EVs are released from the lung into
the circulation during the evolving stage of BPD, and brain neuronal uptake of these EVs results in neural cell
pyroptosis and NDI. We proposed three Specific Aims in the parent grant to test this hypothesis. In
this Administrative Supplement, we will concentrate our research efforts on Specific Aim 1 to further
characterize the sources of EV-ASC and EV-GSDMD, whether they are derived from alveolar epithelial cells
(AEC) or alveolar macrophages (AM). In Specific Aim 2, we will develop new methods to isolate AEC-derived
EVs and AM-derived EVs and determine their effects on brain injury and NDI by adoptive transfer experiments
in newborn mice.

## Key facts

- **NIH application ID:** 10850209
- **Project number:** 3R01HL156803-04S1
- **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:** $105,528
- **Award type:** 3
- **Project period:** 2020-08-05 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850209

## Citation

> US National Institutes of Health, RePORTER application 10850209, Exosomal Gasdermin D Mediated Lung to Brain Crosstalk in Preterm Brain Injury (3R01HL156803-04S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10850209. Licensed CC0.

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