# Role of Liver Kinase B1 in the decreased angiogenesis in bronchopulmonary dysplasia

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $645,450

## Abstract

PROJECT SUMMARY
Bronchopulmonary dysplasia (BPD) is the most common complication of premature birth and increases the risk
of mortality, long-term medical needs, and neuro-developmental impairments. Exposure of preterm lung to
supplemental oxygen (hyperoxia) increases the risk of BPD, due to arrest of alveolar and vascular growth.
Impaired angiogenesis is a key component of this growth arrest in the lung. Lung endothelial cells (LEC) initiate
angiogenesis to establish vascular networks; the mechanisms of decreased angiogenesis in hyperoxia remain
unknown. Our recent studies in a neonatal mouse model of oxygen induced BPD identified decreased expression
of liver kinase B1 (LKB1) in the lungs. LKB1 regulates the function of 5'AMP activated protein kinase (AMPK), a
key metabolic regulator, and the expression of sucrose non fermenter related kinase (SNRK), a novel AMPK
related kinase; both were decreased in hyperoxia exposed lungs. Levels of PGC-1α, an AMPK target required
for mitochondrial biogenesis, were also decreased in hyperoxia exposed lungs. Treatment of mouse pups with
the AMPK activator, metformin, restored mitochondrial biogenesis and angiogenesis in the lung. The mechanistic
link between mitochondrial dysfunction and impaired angiogenesis remains unclear. Endothelial cells (EC)
initiate angiogenesis through commitment to either a migratory, tip cell phenotype which initiates the sprout or a
proliferative stalk cell phenotype that elongates the vascular sprout. Notch ligands determine the EC phenotype
with the tip cells expressing delta like 4 (Dll4) and stalk cells, Jagged1. Our preliminary data show that hyperoxia
increases Dll4 and decreases Jag1 levels in LEC. Based on our pilot data, we hypothesize that the exposure
of preterm lungs to hyperoxia decreases LKB1-AMPK signaling, which leads to decreased mitochondrial
biogenesis and sustained alterations in Notch signaling to impair angiogenesis. We propose two specific aims
to investigate our hypothesis: (1) Determine the mechanism by which hyperoxia decreases LKB1-dependent
signaling and mitochondrial biogenesis. Experiments under this aim will investigate the role of LKB1
downregulation in decreased mitochondrial number and function in hyperoxia, using genetic gain and loss of
function studies in LEC and human pulmonary microvascular endothelial cells and genetically altered mice. (2)
Investigate the role of decreased LKB1-dependent signaling in the impaired angiogenesis in lung during
hyperoxia. Experiments under this aim will investigate the role of LKB1-AMPK downregulation in the decreased
Jag1/increased Dll4 expression and the role of this altered phenotype of EC in decreased angiogenesis in the
lung in hyperoxia. Aim 2 studies will use mice with endothelial specific loss or gain of LKB1, PGC-1α, and Jag1.
Delineation of the mechanisms of decreased angiogenesis in BPD can identify novel therapeutic targets to
restore lung growth in BPD. Since the AMPK activator, metformin is approv...

## Key facts

- **NIH application ID:** 10940315
- **Project number:** 1R01HL174635-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** GIRIJA G. KONDURI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $645,450
- **Award type:** 1
- **Project period:** 2024-07-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940315

## Citation

> US National Institutes of Health, RePORTER application 10940315, Role of Liver Kinase B1 in the decreased angiogenesis in bronchopulmonary dysplasia (1R01HL174635-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10940315. Licensed CC0.

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