Tuesday, May 27, 2025
5/27/2025
NOTCH3 ECD as a Serum Biomarker for Pulmonary Arterial Hypertension - 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.
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