# Shear stress and light-field to elucidate the initiation of cardiac outflow tract

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $459,651

## Abstract

Shear Stress and Light-Field to Elucidate the Initiation of Cardiac Outflow Tract
Biomechanical forces modulate cardiac morphogenesis, and mutations in mechano-sensitive signaling
pathways result in congenital heart defects. During the previous funding cycle, our team custom-built a Light-
Sheet Fluorescence Microscopy (LSFM) with sub-voxel resolution to enhance axial resolution needed to
provide a large field-of-view. This laser optical system allowed for imaging pulsatile vs. oscillatory shear stress-
mediated Notch signaling to initiate endocardial trabeculation. We demonstrated that spatial (/x) and
temporal (/t) variations in shear stress modulates Notch-EphrinB2-Neureguilin-1 signaling in the
endocardium to activate erb-B2 receptor tyrosine kinase (ErbB2) that promotes proliferation of trabeculation.
By integrating LSFM, computation, and transgenic models, we further established that trabeculation dissipates
intracardiac shear stress-generated kinetic energy; thus, mitigating ventricular remodeling. However, it remains
unclear what would be the consequences of reduced myocardial contractility or altered intracardiac flow
dynamics on valve morphogenesis. Thus, we seek to integrate light-sheet (Bessel-Gaussian beam arrays) with
a new 2) light-field (microlens array). The former provides non-diffracting illumination, and the latter provides
volumetric detection as a paradigm shift to image both myocardial contractility and intracardiac flow dynamics
in the outflow tract (OFT). Our preliminary study reveals that shear-mediated Notch1b expression in the
endocardium of OFT regulates endothelial-to-mesenchymal transition (EndoMT); however, the
mechanotransduction causation whereby myocardial contractility and intracardiac shear stress reciprocally
interact to form bicuspid valves and subsequent remodeling to multi-cuspid valves remains elusive. Thus, our
hypothesis is that integration of the new light-field system with imaging computation enhances spatiotemporal
resolution needed to decouple myocardial contraction from intracardiac flow dynamics that modulates
Notch1b-EndoMT to mediate valve morphogenesis in the OFT. In Aim 1, we plan to integrate light-sheet with
the new light-field system for 4-D volumetric imaging of valve formation in the OFT. Our goal is to capture
myocardial contractility and intracardiac shear stress at one snapshot. In Aim 2, we will demonstrate the
interaction between intracardiac shear stress and myocardial contractility underlying valve morphogenesis. Our
goal is to decouple hemodynamic shear from contractile forces that mediate Notch1b-mediated EndoMT. In
Aim 3, we will determine the relative role of shear stress and contractility underlying Notch1b-mediated
EndoMT. Our goal is to elucidate the relative role of contractility and intracardiac stress to transmit Notch1b-
EndoMT signaling underlying bicuspid-valve formation. Overall, our team aims to establish the micro-
environment in which intracardiac flow dynami...

## Key facts

- **NIH application ID:** 10146767
- **Project number:** 2R01HL129727-05A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Tzung K Hsiai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $459,651
- **Award type:** 2
- **Project period:** 2015-07-09 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146767

## Citation

> US National Institutes of Health, RePORTER application 10146767, Shear stress and light-field to elucidate the initiation of cardiac outflow tract (2R01HL129727-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10146767. Licensed CC0.

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