# Endothelial cell- specific Wnt suppression ameliorates vascular inflammation

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $581,352

## Abstract

PROJECT SUMMARY
The overall goal of this proposal is to define the role of the canonical Wnt signaling pathway in endothelial cells
in the development and progression of atherosclerosis. Exciting preliminary data generated through genomic
sequencing experiments show that endothelial GR up-regulates canonical Wnt signaling and that suppression
of Wnt signaling can improve atherosclerosis, quiet inflammation, and restore central endothelial metabolic
defects. The Wnt pathways have recently been implicated in the pathogenesis of atherosclerosis and other states
of vascular inflammation though have not been well-studied in cell-specific environments.
To investigate the effects of endothelial-cell specific canonical Wnt signaling suppression we propose the
following Aims:
In Aim 1, we will characterize the atherosclerotic phenotype of a novel double-mutant mouse model that lacks
the expression of low-density lipoprotein receptor-related protein 5 and 6 (LRP5/LRP6) in endothelial cells.
These are key proteins necessary for canonical Wnt signaling. In addition, we will analyze endothelial cell
inflammation, vascular function, and nitric oxide production in this model. We will also examine markers of fibrosis
and systemic blood pressure.
In Aim 2, our broad goal is to analyze central endothelial metabolism and gene expression in the presence and
absence of Wnt signaling. In Aim 2.1 we plan to evaluate the in vitro metabolic phenotypes of endothelial cells
with suppressed Wnt signaling by assaying fatty acid oxidation, cellular lipid metabolism, mitochondrial
bioenergetics, and fuel preference. In Aim 2.2, we will examine endothelial cell heterogeneity by performing
single-cell RNA-seq from aortas of mice with augmented and suppressed Wnt signaling. These studies will be
extended by examining chromatin capture conformation in key differentially-regulated metabolic genes. These
data sets will be integrated to conclude how chromatin conformation affects the functionality of key genes of
interest.

## Key facts

- **NIH application ID:** 10544011
- **Project number:** 5R01HL131952-07
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Julie Goodwin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $581,352
- **Award type:** 5
- **Project period:** 2016-03-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544011

## Citation

> US National Institutes of Health, RePORTER application 10544011, Endothelial cell- specific Wnt suppression ameliorates vascular inflammation (5R01HL131952-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10544011. Licensed CC0.

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