# Systems Biology Analyses for Hemodynamic Regulation of Vascular Homeostasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $1,062,530

## Abstract

Atherosclerosis is a multi-faceted vascular disease that involves maladaptation of several cell types in the arterial
wall responding to systemic and local factors. During the last two funding cycles, we have used bioinformatics
and system biology approaches together with in vitro and in vivo experimental validations to study the cellular
and molecular mechanisms by which atheroprotective and atheroprone flows regulate the vascular endothelial
cell (EC) in health and disease. Our results demonstrate the crucial roles of flow-regulated EC epigenomes and
transcriptomes in the atheroprotective and athero-prone phenotypes. Emerging evidence suggests that the focal
nature of atherosclerosis is linked to EC heterogeneity resulting from interplay between intrinsic EC properties
and extrinsic shear forces. To further advance our understanding on EC heterogeneity in relation to
atherosclerosis, we hypothesize that mediators (e.g., MED-1) coordinate with lineage-dependent transcription
factors (LDTFs, e.g., KLF4) and signal-dependent transcription factors (SDTFs, e.g., SMAD2) to regulate the
spatiotemporal networks of mechanotransduction. The five specific aims proposed to test this novel hypothesis
are: Aim 1. To delineate the spatiotemporal changes in flow-mediated EC epigenomes and transcriptomes with
single-cell resolution; Aim 2. To elucidate the effect of shear stress on interactions between ECs and vascular
smooth muscle cells (SMCs) or macrophages (MØs) with spatial resolution; Aim 3. To characterize the
transcriptomes and the regulating epigenomes in the arterial wall in vivo with spatial resolution; Aim 4. To employ
system biology approaches to compute and integrate data for the construction of temporal and spatial regulatory
networks; Aim 5. To validate the shear stress-regulated EC heterogeneity at the disease level using mouse
atherosclerosis models and human artery disease specimens. With the use of multi-omics platform at single-cell
resolutions, this renewal proposal will decipher the shear stress regulations of the EC heterogeneity and the
consequential phenotypical changes of ECs and neighboring cell types (SMCs and MØs) relevant to
atherosclerosis.

## Key facts

- **NIH application ID:** 10318053
- **Project number:** 2R01HL108735-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SHU CHIEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,062,530
- **Award type:** 2
- **Project period:** 2012-08-24 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318053

## Citation

> US National Institutes of Health, RePORTER application 10318053, Systems Biology Analyses for Hemodynamic Regulation of Vascular Homeostasis (2R01HL108735-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10318053. Licensed CC0.

---

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