# NOTCH3 ECD as a Serum Biomarker for Pulmonary Arterial Hypertension

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $627,186

## Abstract

PROJECT SUMMARY/ABSTRACT
Pulmonary arterial hypertension (PAH) is a progressive and incurable disease involving pathological signaling
between pulmonary arterial smooth muscle cells and endothelial cells. The goal of this project is to study the
NOTCH3 extracellular domain (NOTCH3 ECD) as a serum biomarker for this disease, with the objective of
applying these discoveries and enabling the translation of our findings into clinical practice. The NOTCH3
receptor on vascular smooth muscle cells is activated by Jagged-1 ligand binding, which induces cleavage of
the receptor into two peptide fragments: the NOTCH3 ECD and the intracellular domain (NOTCH3 ICD). The
NOTCH3 ICD translocates to the nucleus and stimulates a signaling cascade that results in PASMC proliferation,
anti-apoptosis, and marks cells destined to become pulmonary neointimal cells. The fate of the NOTCH3 ECD
in the lung is not known and will be the focus of this grant. In preliminary work, we have shown that human PAH
is characterized by the overexpression and increased cleavage of NOTCH3. We have found that the severity of
PAH in humans and pulmonary hypertension in rodents correlates with the amount of NOTCH3 ICD in the lung.
We have demonstrated that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension
in response to hypoxia or SU5416/hypoxic stimulation and that pulmonary hypertension can be successfully
treated in mice and rats by administration of a monoclonal antibody that blocks Jagged-1 binding to Notch3 in
small pulmonary artery smooth muscle cells. We hypothesize that after NOTCH3 cleavage, NOTCH3 ECD is
released into the serum and can serve as a useful non-invasive biomarker for PAH. To this end, we have
developed a novel bioassay to measure NOTCH3 ECD levels in the serum of humans and rodents. To test our
hypothesis, we propose the following specific aims: 1) test whether patients with PAH have elevated levels of
NOTCH3 ECD in their serum and whether this biomarker reliably predicts pulmonary vascular resistance, mean
pulmonary artery pressure, and tricuspid regurgitant velocity in individuals of different races and ethnicities,
sexes, and ages, both at diagnosis and in serial measurements during disease progression, 2) demonstrate that
the serum blood test for NOTCH3 ECD is specific to patients with WHO Group 1 (idiopathic) PAH and can
accurately predict disease progression, irrespective of patient drug regimens, and 3) elucidate the molecular
mechanisms and cellular interactions in the pulmonary arterial wall that lead to release of NOTCH3 ECD into the
serum in this disease. Information gained from the proposed experiments should put forth a unique, simple
blood test for the diagnosis of PAH and augment our understanding of NOTCH3 signaling in this disease.

## Key facts

- **NIH application ID:** 10883504
- **Project number:** 1R01HL169861-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** PATRICIA A THISTLETHWAITE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $627,186
- **Award type:** 1
- **Project period:** 2024-07-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883504

## Citation

> US National Institutes of Health, RePORTER application 10883504, NOTCH3 ECD as a Serum Biomarker for Pulmonary Arterial Hypertension (1R01HL169861-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10883504. Licensed CC0.

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