# Mechanisms of Pulmonary Microbiota-Induced Inflammation and Vascular Dysfunction in Neonatal Lung Injury

> **NIH NIH K08** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $167,616

## Abstract

PROJECT SUMMARY/ABSTRACT:
 This revised NIH K08 proposal describes a 5-year training and research plan for the candidate, a physician
scientist with a long term goal of becoming an independent investigator in the field of neonatal pulmonary
biology with expertise in understanding the role of the pulmonary microbiome in chronic lung disease of
prematurity. To accomplish this goal, he and his mentoring committee put forth an integrated career
development plan encompassing a novel research idea.
 Bronchopulmonary dysplasia (BPD), the most common pulmonary morbidity in extremely preterm infants is
initiated by injury to the immature lung by early neutrophil influx, collagen degradation, remodeling, and arterial
thickening. The candidate has discovered that the airways of newborn infants are not sterile but are occupied by
a diverse microbiome even at birth, and that the microbiome is altered (dysbiosis) during the development of
BPD. He has also recently discovered the role of exosomal microRNAs in BPD prediction and pathogenesis.
His mentors have previously established that the tripeptide N-acetyl proline-glycine-proline (Ac-PGP) derived
from the breakdown of the ECM plays a critical role in various chronic lung diseases by enhancing neutrophilic
inflammation and endothelial permeability. The preliminary data in this proposal indicate that the airways of
infants with BPD which have increased Gammaproteobacteria (¡-Proteobacteria) also have increased levels of
Ac-PGP. Moreover, gain of Ac-PGP function creates the phenotype of BPD in murine models, whereas loss of
Ac-PGP function reverses the BPD phenotype. Matrix metalloproteinase 9 (MMP9) and prolyl endopeptidase
(PE) degrade collagen, leading to the release of Ac-PGP. MMP9 and PE are top predicted targets of exosomal
miR 548m and miR 129-1-3 respectively and both these miRs are reduced in BPD. Collectively, these findings
lead to the novel mechanistic hypothesis that ¡-Proteobacteria-induced reduction in exosomal miRs
increase protease levels which in turn increase Ac-PGP release and cause chronic neutrophilic
inflammation and vascular dysfunction in BPD. In addition to determining these mechanisms (Aim 1), the
candidate will conduct a human study using independent ‘Discovery’ and ‘Validation’ cohorts of extremely
preterm infants to test the hypothesis that decreased exosomal miRs 548m and miR 129- 1-3p and increased
MMP9, PE and Ac-PGP, in relation to a dysbiotic airway microbota are early predictors of severe BPD (Aim 2).
Thus the work proposed in this research proposal will generate novel information about the mechanisms of
microbiota induced neutrophilic inflammation and vascular dysfunction in BPD, and will determine novel early
biomarkers for BPD.
 The candidate has already assembled a research advisory committee with complementary intellect and
content expertise that can guide him throughout the award period. In addition, the candidate will obtain didactic
education to gain requisite knowled...

## Key facts

- **NIH application ID:** 9859451
- **Project number:** 5K08HL141652-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Charitharth Vivek Lal
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $167,616
- **Award type:** 5
- **Project period:** 2019-02-03 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859451

## Citation

> US National Institutes of Health, RePORTER application 9859451, Mechanisms of Pulmonary Microbiota-Induced Inflammation and Vascular Dysfunction in Neonatal Lung Injury (5K08HL141652-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9859451. Licensed CC0.

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