# Mechanistic and Translational Determination of PERK-targeting Strategies for Non-surgical Management of Abdominal Aortic Aneurysm

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $678,529

## Abstract

Project Summary
Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with high lethality upon aneurysm
rupture, which is particularly prevalent in the aged population. Surgical repairs, albeit invasive and risky,
remain the only treatment option, with no pharmacotherapies clinically available. Thus, there is a compelling
unmet clinical need to discover non-invasive strategies to slow down or even reverse the progression of AAA
lesions. We contend that the first AAA drug therapy will only arise through discoveries of both effective drug
targets and innovative delivery methods. A growing body of evidence reveals that degenerative smooth muscle
cells (SMCs) orchestrate AAA pathogenesis and progression. The dying SMCs incite deleterious dialogues
with endothelial cells and macrophages, weakening the aortic wall while propagating inflammation. Our
exciting preliminary data indicates that the Protein Kinase R-like ER Kinase (PERK) arm of the endoplasmic
reticulum (ER) stress response pathway is a potent driver of SMC degeneration and hence a potential target
for AAA intervention. We found that either pharmacological inhibition or genetic silencing of PERK blocked
SMC degeneration and ameliorated mitochondrial dysfunction in vitro. Moreover, SMC-specific deletion of
PERK profoundly reduced the incidence of aortic aneurysm as well as the rupture risk in an angiotensin (Ang)II
model in male mice. Importantly, we also conceived a biomimetic, reactive oxygen species (ROS)-detonable,
and size-tunable “cluster bomb” nanodesign that uniquely caters to AAA-targeted delivery of versatile
therapeutic payloads, either hydrophobic PERK inhibitors or siRNAs. This platelet membrane coated
nanoplatform demonstrated excellent AAA homing, aortic wall penetration, and when loaded with a selective
PERK inhibitor, halted the progression of pre-existing AAA lesions in a murine model induced by elastase
challenge. These preliminary findings and published evidence lead to our central hypothesis: PERK is a key
driver of SMC degeneration and AAA pathology; and PERK-targeting therapy — enabled through a multi-
modal “cluster bomb” nanoplatform — can lead to effective stabilization or even regression of pre-existing AAA
lesions. To test this hypothesis, we will determine the specific role of PERK in SMC degeneration and the
underlying mechanisms such as PERK-mediated mitochondrial dysfunction (Aim 1a), as well as its role in the
onset and propagation of experimental AAA in two distinct murine models (Aim 1b). We will also develop highly
innovative multi-modal “cluster bomb” nanoplatforms to encapsulate PERK small molecule inhibitors (Aim-2a)
or siRNAs (Aim-2b) and evaluate their utility for PERK-targeting AAA therapies in murine models. Thus, a
unique strength of this proposal is the combined innovations in both drug target and delivery method. The
ultimate product will be a new paradigm in non-invasive management of AAA, which is expected to significantly
reduce th...

## Key facts

- **NIH application ID:** 10881833
- **Project number:** 1R01HL167902-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** SHAOQIN - GONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,529
- **Award type:** 1
- **Project period:** 2024-04-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881833

## Citation

> US National Institutes of Health, RePORTER application 10881833, Mechanistic and Translational Determination of PERK-targeting Strategies for Non-surgical Management of Abdominal Aortic Aneurysm (1R01HL167902-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10881833. Licensed CC0.

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