# Novel exosomal niches for alveolar stem cell-based repair of ARDS

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH CTR AT TYLER · 2022 · $469,701

## Abstract

Summary. The regulation of alveolar regeneration of injured lungs by exosomal signals in acute respiratory
distress syndrome (ARDS) are incompletely studied. We have identified exosomal proteins in bronchoalveolar
lavage fluid (BALF) of ARDS patients that are closely association with the severity of lung injury. In ARDS, clinical
severity is graded by the ratio of arterial oxygen tension (PaO2 in mmHg) to the fraction of inspired oxygen (FiO2).
We have identified stem cell-related niche proteins that are present in mild (200£PaO2/FiO2<300 mmHg) to
moderate ARDS (100£PaO2/FiO2<200 mmHg) but reduced in severe ARDS (PaO2/FiO2<100 mmHg). A key
pathological process in ARDS is damage to the alveolar epithelium, which has been demonstrated in numerous
preclinical and clinical studies to be associated with ARDS severity. Therefore, we hypothesize that exosomal
signals for lung stem cell-mediated re-alveolarization are determinants of ARDS outcomes. Several
findings support this hypothesis. 1) Exosomes are effective autocrine/paracrine pathways for stem cell lineage
in injured organs. 2) Exosomal proteins are protected from catalysis by enzymes in inflamed tissues. 3) Unbiased
high throughput proteomic analysis and advanced bioinformatic platforms have successfully identified novel
biomarkers for other diseases. 4) Although the etiologies of ARDS are diverse, the repair processes mediated
by epithelial stem/progenitor cells regulated by niches seem to be similar based on preclinical studies. Our
objective is to test this hypothesis with BALF samples and patients' clinical data from NIH/NHLBI-supported
clinical trials, prioritize niche molecules, and validate the results in genetically bioengineered mice and organoids
of alveolar type 2 (AT2) epithelial cells. We will apply novel “exosomics” approaches, cutting-edge bioinformatics,
three-dimensional culture models, robust cell origin tracking, and supervised machine learning algorithms. There
are three specific aims: Aim 1 is designed to identify exosomal signaling pathways and networks in lavage that
regulate the lineage of lung stem cells for re-alveolarization. We hypothesize that stem cell-mediated re-
alveolarization has been suppressed in severe ARDS patients due to the disruption of key exosomal niches. We
will prioritize differentially expressed exosomal proteins and related signaling pathways and networks using R
packages. Aim 2 is designed to detect and optimize regenerative predictors for re-alveolarization of injured lungs.
We hypothesize that the significantly differential exosomal molecules in lavage will be associated with clinical
data in ARDS patients. We will perform unbiased clustering and supervised machine learning algorithms to
develop models for discovering critical signals for lung regeneration. The prioritized exosomal predictors will be
compared with traditional whole-protein markers for accuracy and applicability. Aim 3 will validate selected
exosomal signals for AT2-mediated re-...

## Key facts

- **NIH application ID:** 10443132
- **Project number:** 2R01HL134828-05A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH CTR AT TYLER
- **Principal Investigator:** HONG-LONG JI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $469,701
- **Award type:** 2
- **Project period:** 2017-09-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443132

## Citation

> US National Institutes of Health, RePORTER application 10443132, Novel exosomal niches for alveolar stem cell-based repair of ARDS (2R01HL134828-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10443132. Licensed CC0.

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