# Integrative Multiomics to Uncover Novel Genes and Networks in Pulmonary Arterial Hypertension

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $176,580

## Abstract

Project Summary/Abstract
This proposal describes a mentored physician-scientist training program to uncover novel genes and networks
in pulmonary arterial hypertension (PAH) using an integrative multiomics approach. The candidate is currently
developing his academic career in the Division of Pulmonary & Critical Care at the David Geffen School of
Medicine of UCLA. His long-term goal is to develop more effective targeted therapies for PAH patients informed
by a deeper knowledge of the pathogenic mechanisms. Under the guidance of his mentors Drs. Mansoureh
Eghbali and Xia Yang, the candidate will develop a unique cross-disciplinary skillset in integrative systems,
single-cell, spatial and experimental biology that will facilitate his transition to research independence in the field
of PAH.
PAH remains an incurable disease characterized by irreversible pulmonary vascular remodeling, poor quality of
life, and guarded long-term prognosis. Leveraging a well-powered cohort integrating the latest omics and
computational methodologies is critically needed to identify candidate molecular drivers in PAH lungs as potential
therapeutic targets. With access to RNA sequencing of the largest biobank of human PAH and control lungs to
date (n=148), we have identified, by co-expression network analysis, a module of 266 genes (which we refer to
as the “pink” module) that is strongly associated with PAH lungs. Through multimodal integration with right heart
catheterization data, histological analyses, and genome-wide association studies (GWAS), we found the pink
module is not only transcriptionally upregulated in PAH lungs, but also associated with increased hemodynamic
severity, vascular remodeling, and genetic risk of PAH. Our preliminary data suggests pink module genes are 1)
dysregulated in pulmonary vascular cells, 2) enriched in pathways relevant to pulmonary vascular remodeling
such as endothelial-mesenchymal transition and Wnt signaling, 3) and may be candidate molecular drivers of
PAH, such as ANTXR1, an integrin-like glycoprotein strongly implicated in various cancers but never studied in
PAH. Given the mounting preliminary evidence for the importance of the bulk lung-derived pink module, a deeper
investigation into its cell-specific role in PAH pathogenesis is needed to advance our understanding of the
molecular drivers of PAH lungs and identify new therapeutic targets. We hypothesize that the pink module drives
vascular remodeling in PAH through its dysregulation within pulmonary vascular cells. To test this hypothesis,
we will 1) resolve the specific cellular context in which the pink module is dysregulated in PAH lungs using single-
nucleus RNAseq and spatial transcriptomics and 2) determine the effects of in vitro knockdown of a pink module
candidate driver gene, such as ANTXR1, in PAH pulmonary vascular cells. The proposed studies will utilize a
combination of cutting-edge multiomic approaches and experimental biology to provide greater insight into a...

## Key facts

- **NIH application ID:** 10723950
- **Project number:** 1K08HL169982-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Jason Hong
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $176,580
- **Award type:** 1
- **Project period:** 2023-08-10 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10723950

## Citation

> US National Institutes of Health, RePORTER application 10723950, Integrative Multiomics to Uncover Novel Genes and Networks in Pulmonary Arterial Hypertension (1K08HL169982-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10723950. Licensed CC0.

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