# The Cellular Response to Elafin in PAH

> **NIH NIH P01** · STANFORD UNIVERSITY · 2020 · $701,561

## Abstract

Project 1 builds upon exciting preclinical studies showing efficacy of daily subcutaneous administration of an
elastase inhibitor, human recombinant Elafin, in reversing a severe model of pulmonary hypertension in rats.
Elafin also induces significant regression of neointimal lesions in pulmonary arteries (PA) in explants from
lungs of patients with pulmonary arterial hypertension (PAH), and unexpectedly improved deficient BMPR2
signaling in endothelial cells (EC) from patients with PAH by recruiting BMPR2 receptors to caveolae.
Moreover, the elevated circulating levels of neutrophil elastase that Elafin would be expected to inhibit and the
favorable toxicity and pharmacokinetic profile of Elafin, have led us to address the biology of Elafin, in a
manner, we hypothesize, that will attribute Elafin efficacy in PAH to its properties of subverting the adverse
functions of neutrophils (PMN) and of reversing vascular cell dysfunction. In Aim 1, we will investigate the role
of Elafin in controlling abnormal PAH PMN function and PAH PMN-PAEC interactions under static conditions,
of flow as well as laminar and disturbed flow. To investigate the mechanisms involved we will use a candidate
approach, as well as RNA Seq and assays of transposase accessible chromatin (ATAC Seq), applicable to
small numbers of PA EC under conditions of static, laminar and disturbed flow. In Aim 2, we will determine
whether promising preliminary studies that show an Elafin-responsive phenotype in native PAEC that is
reproduced in iPSC-EC from the same patients is true for a larger cohort. We will then relate the biologic
improvement with Elafin to a gene expression signature. We will generate iPSC-EC from patients in the Phase
1 and 2 Clinical Trials in Project 3, and correlate biologic measurements of the iPSC-EC response to Elafin
with gene expression and with clinical outcome as this relates to Elafin responders vs. non-responders.
In Aim 3 we will cast a wider net for Elafin function in cells as we delineate the Elafin interactome in PMN and
PAEC. This will be accomplished by immunoprecipitation (IP) with labeled Elafin and mass spectrometry to
identify the interacting proteins. Once validated by co-IP, the impact of Elafin has on the function of the
interacting protein will be assessed. In Aim 4, we will build upon compelling preliminary data showing the
impact of a novel mass spectrometry-flow cytometry hybrid technology (CyTOF) in identifying a pan-PAH
signature that suggests activation of CD4+CD25hi cells, and will determine the extent to this and other
abnormalities can be normalized ex vivo by Elafin both acutely and in patients with PAH following chronic
treatment. We will relate CyTOF to the biology and the state of activation of cells within the perivascular niche,
using multiplex ion beam imaging (MIBI). The studies proposed allow an unprecedented opportunity to
advance knowledge in the broader fields of PMN-EC interaction, flow dependent EC gene and epigenetic
re...

## Key facts

- **NIH application ID:** 9970521
- **Project number:** 5P01HL108797-09
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Marlene Rabinovitch
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $701,561
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970521

## Citation

> US National Institutes of Health, RePORTER application 9970521, The Cellular Response to Elafin in PAH (5P01HL108797-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9970521. Licensed CC0.

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