# 3'UTR Shortening In Pulmonary Vascular Disease

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $340,796

## Abstract

Project Summary
Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain that affects 35 million people in
the world and 5.5 in the USA. AD is the most common form of dementia accounting for up to 56% of cases
years after diagnosis. Limited therapies are available for AD and they do not delay or halt the progression of
disease and thus new treatments are urgently needed. AD is characterized by the accumulation of cerebral
plaques composed of amyloid-β (Aβ), which is believed to be an early pathogenic event. Most cases of AD are
sporadic and develop after the age of 65 years. Recent studies have indicated an overall impairment in Aβ
clearance, rather than Aβ overproduction to be critical in AD. One of the most common observations in AD,
present in up to 98% of AD patients, is the presence of cerebral amyloid angiopathy (CAA). A recent study has
demonstrated that vascular smooth muscle cells (VSMCs) in the brain are capable of mediating local clearance
of Aβ. CAA is also a major trigger of intracranial hemorrhage a feature of cerebrovascular disease (CVD). This
is significant since there is a large body of literature demonstrating a link between CVD and AD and its
correlation with dementia. Despite the importance of the vasculature in AD, the link between Aβ clearance
through VSMCs and increased CVD leading to dementia is not fully understood. NUDT21, also known as
cleavage factor 25 (CFIm25), is an RNA binding protein that when depleted leads to alternative
polyadenylation (APA) and global 3'UTR shortening. Our research on NUDT21 has revealed that depletion of
NUDT21 is present in the brains of patients with AD and leads to alterations in protein transport and
processing pathways in vascular smooth muscle cells (VSMCs). Our overall hypothesis is that loss of cerebral
vascular smooth muscle NUDT21 disrupts Aβ clearance and predisposes the brain to CVD. This will be tested
in the following Specific Aims: 1- Evaluate the role of NUDT21 loss and 3'UTR landscape in AD; 2- Determine
whether NUDT21 depletion promotes CAA and 3- Assess whether NUDT21 depletion exacerbates
cerebrovascular disease (CVD). Successful completion of these experiments is expected to reveal new
insights into the pathogenesis of AD and AD related dementias (ADRD). Specifically, this proposal aims to
uncover novel pathways related to vascular Aβ clearance and predisposition to CVD linked by APA induced by
loss of NUDT1. These concepts have not been fully explored in AD thus; this proposal has the potential to
stimulate additional activity leading to progress on AD and ADRD.

## Key facts

- **NIH application ID:** 10285407
- **Project number:** 3R01HL138510-05S1
- **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:** $340,796
- **Award type:** 3
- **Project period:** 2017-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285407

## Citation

> US National Institutes of Health, RePORTER application 10285407, 3'UTR Shortening In Pulmonary Vascular Disease (3R01HL138510-05S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10285407. Licensed CC0.

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