# Nucleolin Regulation of miRome by Shear Stress

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $583,826

## Abstract

The focal distribution of atherosclerotic lesions in the arterial tree is attributable to the exposure of the vascular
endothelial cells (ECs) to the atheroprone oscillatory shear (OS) at vessel branch points and curvatures, in
contrast to the atheroprotective pulsatile shear (PS) at straight parts of the vessel. These two types of flow
patterns induce distinct expression profiles of miRNAs (miRs) that differentially regulate the expression of target
geness, resulting in distinct functional outcomes. Nucleolin (NCL) is a multi-functional protein that plays critical
roles in regulating cell functions through epigenetic, transcriptional, post-transcriptional, and translational
regulations. We propose that NCL regulates miRome (miR transcription and maturation) through its interactions
with DNA (via g-quadruplex sequences) and RNA (via UCCCGA consensus sequence). Our preliminary results
have demonstrated that PS induces the phosphorylation of NCL that leads to an increased binding of NCL to the
promoter/enhancer regions of miR23b/27b to increase miR transcription. On the other hand, under OS, the non-
phosphorylated NCL binds to miR93/miR484 and Drosha to facilitate miR maturation. These novel findings have
led to the hypothesis of this renewal proposal: NCL is differentially regulated by atheroprotective and
atheroprone flow patterns to modulate the miRome at transcriptional and maturation levels, thus playing
an important role in vascular homeostasis in health and disease. To test this hypothesis, we propose the
following four Specific Aims: 1) to examine the molecular mechanisms underlying PS- vs. OS-regulation of NCL
in miR transcriptome, 2) to determine the molecular mechanisms underlying PS- vs. OS-regulation of NCL-
modulated miR maturation, 3) to integrate the multi-layer regulations of miRome by NCL and the functional
consequences under PS and OS with the use of systems approaches, 4) to validate the role of NCL in regulating
vascular function in vivo. In the proposed research, we will use a combination of in vitro endothelial cell biology,
in vivo mouse models, in silico network construction/data mining, and clinical samples derived from patients with
cardiovascular diseases to decipher the mechanisms of flow modulation of NCL-regulation of miRome. The
findings will result in novel understanding of the role of NCL in regulating vascular functions in health and disease
via miR regulations.
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## Key facts

- **NIH application ID:** 10065006
- **Project number:** 5R01HL106579-11
- **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:** $583,826
- **Award type:** 5
- **Project period:** 2011-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065006

## Citation

> US National Institutes of Health, RePORTER application 10065006, Nucleolin Regulation of miRome by Shear Stress (5R01HL106579-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10065006. Licensed CC0.

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