# 3'UTR Shortening in Pulmonary Vascular Disease

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $388,764

## Abstract

Project Summary
Pulmonary hypertension (PH) is a disorder of the lung vasculature defined by increased mean pulmonary arterial
pressure (mPAP) leading to right ventricle (RV) hypertrophy and dysfunction, right-sided heart failure and
ultimately death. The pathologic process in PH is characterized by extensive vascular remodeling affecting
pulmonary artery smooth muscle cells (PASMC) and the RV wall. Several process have been associated with
the development of pulmonary hypertension including increased perivascular fibro-proliferative deposition
altered cellular metabolism and increased cell proliferation and resistance to apoptosis. Recent advances in the
field of RNA biology have shown that alternative polyadenylation (APA) results in shorter 3'-untranslated regions
(3'UTR) of mRNAs that can avoid mRNA regulation resulting in overexpression of these transcripts. Recent
studies have shown that 3'UTR is present following cellular stress. Depletion of a 25kDa subunit of the RNA
binding protein cleavage factor I (CFIm25), has been shown to result in APA and marked 3'UTR shortening.
Provocative preliminary data from my lab demonstrate depletion of CFIm25 and evidence of 3'UTR shortening
from isolated pulmonary arteries from models of pulmonary hypertension. These observations are in line with
evidence of 3'UTR shortening in isolated pulmonary artery smooth muscle cells. However, the effects of 3'UTR
shortening in PH remain unknown. Pathway analysis from CFIm25 knock-down studies in PASMCs revealed
3'UTR shortening of genes associated with fibro-proliferative deposition and cellular proliferation. Taken
together, our hypothesis is that 3'UTR shortening alters gene expression of many factors influencing the
development of PH. Aim 1 will address how temporal changes in CFIm25 depletion lead to increased vascular
remodeling through 3'UTR shortening. We will also evaluate expression levels of CFIm25 using patient-derived
tissues and PASMCs to track how depletion of CFIm25 correlates with disease severity in PH. Using novel RNA-
seq approaches in murine and human tissue we aim to identify changes in 3'UTR length in pathways contributing
to the development of PH. In Aim 2, we will evaluate how CFIm25 depletion in vascular smooth muscle cells
worsens the development of PH. Here we will also perform novel RNA-seq approaches to identify shortened
3'UTRs following depletion of CFIm25. Aim 3 will determine the levels of miRs-203 and miR-509-3p in patients
with PH and in experimental models of PH. We will test the therapeutic potential of strategies aimed at elevating
CFIm25 expression as a novel treatment for PH.

## Key facts

- **NIH application ID:** 10143281
- **Project number:** 5R01HL138510-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Harry Karmouty-Quintana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,764
- **Award type:** 5
- **Project period:** 2017-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143281

## Citation

> US National Institutes of Health, RePORTER application 10143281, 3'UTR Shortening in Pulmonary Vascular Disease (5R01HL138510-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10143281. Licensed CC0.

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