# Pulmonary vascular glutamine metabolism at the intersection of hemodynamic forces and smooth muscle proliferation in congenital heart disease

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $174,798

## Abstract

PROJECT SUMMARY/ABSTRACT
In children with congenital heart disease (CHD) there is an unidentified biological switch that drives a biologic
transformation towards self-sustaining and progressive pulmonary arterial hypertension (PAH). In advanced
disease, PAH secondary to CHD shares biologic similarities with other PAH groups. However, the signaling and
metabolic derangements that drive early pulmonary vascular disease remain obscure, and currently available
therapies largely fail to address the underlying pathologic origins of disease. My long-term research objective is
to define the biochemical mechanisms by which aberrant pulmonary vascular hemodynamics initiate and drive
pulmonary vascular dysfunction in CHD. The specific purpose of this application is to describe early metabolic
and mechanotransductive signaling derangements in pulmonary vascular smooth muscle exposed to pulmonary
overcirculation, and define their contributions to an abnormal vascular growth phenotype. Based on previously
published work and novel preliminary data presented with this application, we hypothesize that exposure of
pulmonary vascular smooth muscle to excessive pressure and blood flow results in sustained abnormalities of
mechanotransductive signaling that perpetuate changes in cellular glutamine and cholesterol metabolism,
promoting a dysregulated proliferative phenotype. In order to test this hypothesis, we are using a unique and
clinically relevant animal model of CHD that recapitulates an early and progressive phase of disease that is
poorly represented in other disease models. Our specific aims are to: 1) determine the role of altered glutamine
and cholesterol metabolism in facilitating an abnormal proliferative phenotype in shunt pulmonary artery smooth
muscle cells (PASMCs); 2) define the initiating and sustaining mechanisms that promote increased YAP
signaling in shunt PASMCs and delineate the role of YAP in altered cellular metabolism and proliferation; and 3)
evaluate metabolic biomarkers and therapeutic targets in a pre-clinical translational model of CHD. We will
perform parallel C13 stable isotope resolved flux of glutamine and glucose, and conduct targeted manipulation
of glutamine metabolism and cholesterol biosynthetic pathways to evaluate the impact on cellular proliferation.
We will use a novel microfluidic cell culture bioreactor to assess the initiating and sustaining mechanical stimuli
that induce the mechanosensitive transcriptional regulator YAP in shunt smooth muscle. We will also delineate
the role of YAP in altered vascular smooth muscle metabolism and proliferation by targeted genetic knockdown
of YAP and ChiP analysis. Finally, we will conduct translational evaluations of identified metabolic biomarkers
and metabolic focused therapies in our model of CHD. The structured experience outlined in this proposal will
solidify the knowledge and skills I require to transition to an independent research career and attain my long term
scientific an...

## Key facts

- **NIH application ID:** 10892703
- **Project number:** 5K08HL148512-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jason Boehme
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $174,798
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892703

## Citation

> US National Institutes of Health, RePORTER application 10892703, Pulmonary vascular glutamine metabolism at the intersection of hemodynamic forces and smooth muscle proliferation in congenital heart disease (5K08HL148512-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10892703. Licensed CC0.

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