# IL-1R1 in Endothelial-to-Mesenchymal Activation

> **NIH HL R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2026 · $446,848

## Abstract

PROJECT SUMMARY:
Endothelial-to-mesenchymal transition (EndMT) has been detected in atherosclerosis, and the extent of EndMT
observed in the human plaques strongly correlates with the severity of the disease, implying clinical relevance
of EndMT in the pathogenesis of atherosclerosis. Both disturbed blood flow (d-flow) and interleukin-1 signaling
(IL-1) have been implicated in EndMT formation. The signaling pathway that links d-flow and EndMT is still
unclear. Moreover, IL-1 as a therapeutic target has already been tested and the Canakinumab Anti-inflammatory
Thrombosis Outcome Study (CANTOS) assessed the therapeutic effect of the anti-IL-1β antibody in patients
after myocardial infarction and showed 31% reduction of cardiovascular and all-cause mortality. However, some
of those patients developed immunosuppressive off-target effects. In addition, there is no clear principal cell type
in human severe atherosclerosis responsible for IL-1 signaling. Our recently published work has demonstrated
that d-flow induces activation of interleukin-1 receptor signaling kinase (IRAK1) within endothelial cells (ECs),
with an increase in p-IRAK1 levels in human and mouse atherosclerosis. IRAK1 is co-expressed with EndMT in
severe atherosclerosis, and deletion of IRAK1 decreases EndMT in vitro, identifying a novel role for IRAK1 as a
downstream effector in d-flow-induced EndMT. Our central hypothesis is that IRAK1 activation mediates d-
flow-induced EndMT and selective inhibition of IRAK1 will allow efficient inhibition of atherosclerosis without
promoting significant immunosuppression. Aim 1 Determine the mechanistic role of IRAK1 activation in
oscillatory flow-induced EndMT. Our preliminary data supports IRAK1 activation by d-flow and that mediates
EndMT formation. Aim 1.1, utilizing CRISPR Cas-9 KO selective deletion and re-expressing vectors, we will test
the role of IRAK1 in oscillatory flow-induced EndMT. In Aim 1.2, we will evaluate the activating roles of IRAK1
domains by t

## Key facts

- **NIH application ID:** 11264941
- **Project number:** 5R01HL172846-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Mabruka  Alfaidi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** HL
- **Fiscal year:** 2026
- **Award amount:** $446,848
- **Award type:** 5
- **Project period:** 2024-03-01T00:00:00 → 2029-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11264941

## Citation

> US National Institutes of Health, RePORTER application 11264941, IL-1R1 in Endothelial-to-Mesenchymal Activation (5R01HL172846-03). Retrieved via AI Analytics 2026-05-20 from https://api.ai-analytics.org/grant/nih/11264941. Licensed CC0.

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