# Endothelial cell dysfunction in cerebral aneurysm pathogenesis

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $497,786

## Abstract

Project Summary/Abstract:
Endothelial dysfunction is highlighted as an early marker of vascular abnormality preceding
cerebral aneurysm formation, but the molecular events behind this transformation remain
unclear. Inflammatory cytokines including interleukin-2 (IL-2) mediate vascular disease, but its
role in cerebral aneurysm pathophysiology is unknown. Our preliminary data indicate that IL-2 is
expressed in human cerebral aneurysm tissue and induces a phenotypic switch in endothelial
cell (EC) function from the maintenance of vasomotor activity, to promotion of inflammation and
matrix remodeling. We have also found that inhibition of the IL-2 target protein mTOR with
rapamycin reduced aneurysm progression and rupture in a mouse cerebral aneurysm model.
Collectively this preliminary data suggests a vital role of the IL-2/mTOR pathway in aneurysm
progression. The objective of this grant is to characterize the role of IL-2 activated mTOR in EC
dysfunction and aneurysm development and progression. The central hypothesis of this
proposal is that IL-2/mTOR inhibition promotes repopulation of EC and decreases inflammation,
which halts aneurysm progression and promotes vascular healing. In this proposal, we will
determine the role of IL-2 activated mTOR in aneurysm formation, progression, and rupture and
define the mechanisms by which IL-2/mTOR promotes EC dysfunction (Aim 1). We will treat
experimental aneurysms with a novel stent delivering controlled release of the IL-2/mTOR
inhibitor rapamycin to determine if IL-2/mTOR inhibition reverses EC dysfunction while
decreasing inflammation (Aim 2). Finally, we will determine IL-2 expression, mTOR activation
and EC dysfunction in human cerebral aneurysmal tissue and intra-aneurysmal blood and if
rapamycin treatment prior to surgery reduces IL-2/mTOR signaling and EC dysfunction (Aim 3).
The proposed research is innovative in that successful completion of this project will determine
the events behind EC dysfunction which lead to aneurysm progression and will help develop
novel minimally invasive therapeutic strategies for aneurysm obliteration.

## Key facts

- **NIH application ID:** 10755655
- **Project number:** 5R01NS111119-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Robert Michael Starke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $497,786
- **Award type:** 5
- **Project period:** 2021-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755655

## Citation

> US National Institutes of Health, RePORTER application 10755655, Endothelial cell dysfunction in cerebral aneurysm pathogenesis (5R01NS111119-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10755655. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*