# Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis.

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $586,378

## Abstract

Project Summary and Abstract
Despite standard of care, atherosclerotic cardiovascular disease (CVD) remains a leading cause of morbidity
and mortality in the United States. In nearly half of patients, risk of CVD is elevated despite adequate control of
standard risk factors. In this group, inflammation is proposed as a key driver. Despite this insight, no targeted
anti-inflammatory therapies exist for CVD. Thus, an urgent unmet need exists to elucidate novel mechanisms of
chronic inflammation in athersclerosis. The long-term goal of my laboratory is to understand how enhancer
plasticity drives atherosclerosis through effects on gene expression that change cell state. The overall objectives
of this proposal are to 1) to elucidate how inflammatory activation of vascular endothelial cells (ECs) alters EC
identity and 2) to define the role of BRD4 in EC activation in atherogenesis. Our central hypothesis is that
prolonged inflammatory activation by cytokines and proatherogenic lipids directs a durable remodeling of
enhancers such that basal cell state is lost and a new inflammatory cell state is activated. Our hypothesis is
formulated on the basis of our previously published work as well as new preliminary data that reveal the following:
i) chronic inflammatory stimulation of human aortic ECs (HAECs) results in dynamic activation of a subset of
new super enhancers; ii) in HAECs, these new enhancer regions persist despite removing the proinflammatory
stimulus; iii) a core transcription factor (TF) circuitry can be inferred from sequence-specific TF motifs that are
enriched at chronic inflammatory super enhancers; iv) BRD4 inhibition blocks leukocyte recruitment in peritonitis
and atherogenesis in part through EC effects. The rationale for this project is that a deeper understanding of the
molecular mediators of chronic inflammation holds the promise of identifying new drug targets designed to
reverse the long-term, pathologic activation of vascular cells that drives atherosclerosis. To achieve our overall
objectives, we will pursue the following integrated, but non-interdependent specific aims: 1) To determine how
chronic, proatherogenic stimuli remodel chromatin structure and unveil new enhancers in human arterial ECs
and 2) To determine the functional role of Brd4 in maintaining EC state during atherogenesis in vivo. The overall
contribution of this work will be to elucidate how chronic inflammatory signaling establishes a new endothelial
cell state through persistent enhancer activation. The central innovation of this proposal is a conceptual shift in
research paradigm by demonstrating inflammation drives pathologic cell states in atherosclerosis by a dynamic
interplay between chromatin structure, enhancer function and gene expression.

## Key facts

- **NIH application ID:** 10136077
- **Project number:** 5R01HL146654-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** JONATHAN David BROWN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $586,378
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136077

## Citation

> US National Institutes of Health, RePORTER application 10136077, Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis. (5R01HL146654-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136077. Licensed CC0.

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