# Evaluation of the Dynamic Reciprocity Between Cells and the Vessel Matrix in Pulmonary Hypertension

> **NIH NIH P01** · UNIVERSITY OF COLORADO DENVER · 2024 · $429,154

## Abstract

There is growing evidence of the role of inflammation as a trigger and enhancer of pulmonary vascular
remodeling in pulmonary hypertension (PH). This PPG focuses on the role of complement as a trigger of
pulmonary vascular disease and PH. The overall guiding concept for Project 3 is the key angle of disease
heterogeneity at multiple levels: at the whole diseased human lung level, lesional level in a diseased lung, at
the level of similar lesions among IPAH lungs, and animal models of PH. It is the central goal of this Proposal to
provide the significance of the mechanistic studies developed in Projects 1,2, and 4.
Our central hypothesis is that key molecular fingerprints including RNA expression and cellular combined
with extracellular proteomes can be used to define molecularly specific pulmonary vascular lesions in
PAH. These profiles will reflect prolonged activation of complement and the subsequent remodeled
perivascular environment. We rely on a comprehensive approach based on interrogation of human diseased
and control lungs, and plasma of a large cohort of well characterized IPAH patients and controls (Aim 1), robust
models of severe PH (Aim 2), and mechanistic investigations in the bovine model of hypoxic PH (Aim 3), using
high throughput approaches of genomics, proteomics, and immune localization at the lung tissue level.
Specifically, AIM 1 will test the hypothesis that there is evidence of complement activation in IPAH pulmonary
vascular lesions, which are related to specific proteomic and genomic fingerprints; AIM 2 will Identify shared
molecular signatures established from the human IPAH as compared with the bovine and rat SU5416 models of
PH, with a focus on prioritization of therapeutic strategies targeting complement and extracellular matrix
remodeling; and, AIM 3 will test the hypothesis that blockade of complement in a large animal model of PH will
lead to decreased proinflammatory microenvironment and normalization of the pulmonary vascular proteome.
This proposal is highly significant as it addresses the key aspect of molecular heterogeneity among pulmonary
vascular lesions and among patients, and animal models; it serves to provide a central translational angle to
mechanistic studies in Projects 1,2, and 4 as it seeks to identify complement activation markers in diseased
human tissue and robust models of disease. Moreover, it will provide evidence linking complement blockade in
reverting a PH proinflammatory phenotype and PH proteome. Project 3 introduces highly novel approaches,
including the assessment of the proteome and transcriptome at the lesional level, high throughput
immunofluorescence imaging at the tissue level, and novel approaches to block complement.

## Key facts

- **NIH application ID:** 10911064
- **Project number:** 5P01HL152961-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Rubin M. Tuder
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,154
- **Award type:** 5
- **Project period:** 2020-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911064

## Citation

> US National Institutes of Health, RePORTER application 10911064, Evaluation of the Dynamic Reciprocity Between Cells and the Vessel Matrix in Pulmonary Hypertension (5P01HL152961-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10911064. Licensed CC0.

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