# AMP Kinase regulation in persistent pulmonary hypertension of the newborn

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $380,000

## Abstract

Project Summary
Persistent pulmonary hypertension of the newborn (PPHN) is a life threatening condition which results from
failure of pulmonary vascular resistance to decrease at birth. The affected infants are hypoxemic and have an
increased risk of death or long-term impairments for survivors. Recent studies identified 2 key alterations in
PPHN lungs: (1) a decrease in mitochondrial biogenesis and oxidative phosphorylation in the pulmonary artery
endothelial cells (PAEC) and (2) a decrease in angiogenesis, which contributes to failure of postnatal
adaptation of pulmonary circulation. The overall objective of this research project is to identify mechanisms that
underlie these 2 key alterations in PPHN. Preliminary studies conducted for this project identified decreased
expression of liver kinase B1 (LKB1), a key upstream regulator of the energy sensor, 5’AMP activated protein
kinase (AMPK) in PPHN. This alteration contributes to decreased expression of PGC-1α, a transcription
cofactor required for mitochondrial biogenesis. Consistent with these changes, mitochondrial biogenesis is
decreased in PPHN. In contrast, levels of hypoxia sensor, HIF-1α are increased in PPHN endothelial cells,
leading to increase in glycolysis. The PAEC in PPHN show a switch in phenotype to predominantly tip cells
from proliferative stalk cells. Whether the altered LKB1-PGC-1α signaling contributes to this phenotype switch
is unknown. Studies proposed in this application investigate the hypothesis that decreased LKB1-PGC-1α
signaling impairs mitochondrial biogenesis in PAEC and the resulting switch to glycolysis alters the PAEC
phenotype specification to impair angiogenesis during a critical window of lung development. The hypothesis
will be tested by 2 specific aims: (1) Investigate the role of decreased LKB1-PGC-1α signaling in the impaired
mitochondrial biogenesis and increased HIF-1 α levels in PPHN and (2) Investigate the role of decreased
LKB1-PGC-1α signaling in the PAEC phenotype switch and impaired angiogenesis in PPHN. The proposed
studies will be done in fetal lambs with PPHN induced by prenatal constriction of ductus arteriosus, a known
mechanism of PPHN. Completion of these studies will delineate the mechanism of increased pulmonary
vascular resistance in PPHN. These studies will also provide the scientific rationale for testing therapeutic
agents to increase LKB1 - PGC-1α signaling and cell permeable metabolic intermediates to restore
angiogenesis in PPHN.

## Key facts

- **NIH application ID:** 10210285
- **Project number:** 5R01HL136597-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** GIRIJA G. KONDURI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,000
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210285

## Citation

> US National Institutes of Health, RePORTER application 10210285, AMP Kinase regulation in persistent pulmonary hypertension of the newborn (5R01HL136597-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10210285. Licensed CC0.

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