# Systems Biology Analyses for Hemodynamic Regulation of Vascular Homeostasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $1,057,617

## Abstract

Hemodynamic regulation is important in endothelium homeostasis. In our first four years of this systems
biology grant, we established the signaling and transcription mechanisms of endothelial cell response to
atheroprotective and atheroprone shear stresses in vitro and in vivo. We have continued to develop the first
dynamical model of EC transcriptome regulated by different shear stresses with an extensive time-series
study. Through which, we have established the significant role of epigenetic modifications, particularly
chromatin remodeling, in EC transcriptome regulations. These findings lead us to hypothesize that
atheroprotective and atheroprone flows induce differential changes in histone modifications and long-range
DNA interactions mediated by long non-coding RNA (lncRNA) to lead to distinct transcriptome underlying
endothelial homeostasis vs. dysfunction. We further hypothesize that these changes are dynamically regulated
to result in distinct temporal signals and gene expression. We propose to study the temporal delineation of the
sequence of events in which signaling leads to chromatin modifications and long-range DNA interaction
followed by transcription, thus causing further translational and post-transcriptional responses, and eventually
normal vs. diseased phenotype. The proposed research will serve as the first multiscale systems study of
endothelial response to shear stress to elucidate the physiological and pathophysiological mechanisms
important for the onset and progression of atherosclerotic diseases. Our goal is to explore the epigenetic
regulation of transcription in mechanistic details, and the specific objectives include the following: 1)
measurement and identification of epigenetic and regulatory factors that differentially regulate EC function
under different shearing conditions (ChIP-seq method), 2) study of chromatin structure and topology on EC
function under shear flows (4C method), 3) integrative analysis of epigenetic and transcriptional data to provide
mechanisms and build dynamical regulatory networks of shear-mediated phenotypes in EC (systems biology
methods), and 4) testing and validation of novel hypotheses of hemodynamic regulation in vitro, in silico and in
vivo using genetic and pharmacological perturbation methods, including studies on normal and diseased artery
tissues from human subjects. We anticipate that the results from this project will provide a comprehensive
multiscale model of flow-mediated functional consequences in ECs for normal and pathophysiology.

## Key facts

- **NIH application ID:** 9999010
- **Project number:** 5R01HL108735-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SHU CHIEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,057,617
- **Award type:** 5
- **Project period:** 2012-08-24 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999010

## Citation

> US National Institutes of Health, RePORTER application 9999010, Systems Biology Analyses for Hemodynamic Regulation of Vascular Homeostasis (5R01HL108735-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999010. Licensed CC0.

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