# Optical Tools to Assess the Role of Cardiac Function in the Development of Congenital Heart Defects

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $743,722

## Abstract

Project Summary
We and others have shown that altered hemodynamics and shear stress can lead to congenital heart defects
(CHDs), but still there is limited information on how these forces affect molecular signaling. Studying the impact
of abnormal hemodynamics and shear stress becomes even more urgent when we consider that perturbed blood
flow may be a contributing factor to a large percentage of CHDs regardless of whether the initial trigger is
environmental or genetic. Although our group and others have recently developed extremely useful optical
imaging tools (e.g., optical coherence tomography – OCT) to assess hemodynamics and shear stress, and
connected these measurements to CHDs, it has been difficult to link shear stress with the affected molecular
pathways. Our group and others have performed qPCR experiments on control and shear-stress perturbed
hearts to see how abnormal hemodynamics alters gene expression. However, this approach requires the entire
embryonic heart for one measurement, missing all spatial and cell-type information, particularly at the
endocardial layer. In order to successfully assess how shear stress affects molecular signaling throughout the
looping heart, we need to improve upon our OCT methods, develop 3D methods for assessing embryonic heart
gene expression, and create an advanced image processing pipeline to analyze data and relate regional shear
stress to gene expression.
 This renewal proposal will continue our work developing tools that can lead to a more sophisticated
understanding of how cardiac function (e.g., hemodynamics and electrical impulse conduction) affects heart
development, enabling potential therapies to avoid or mitigate CHDs. In this proposal, we will focus on developing
tools to understand how oscillatory shear stress (quantified as oscillatory shear index - OSI) influences gene
expression and leads to CHDs. In our preliminary studies, we increased regurgitant blood flow (causing
increased OSI) to show that alterations to OSI leads to smaller cardiac cushions (valve precursors) and
ultimately, to CHDs. Increased regurgitant blood flow and smaller cushions is present in our two disease models
(fetal alcohol spectrum disorders – FASD; velo-cardio-facial syndrome/Digeorge) and our FASD prevention
compounds partially normalize blood flow, cardiac cushion size, and greatly reduce morbidity and CHDs.
 Our specific aims include 1) advance our OCT system and shear stress analysis, 2) develop fluorescence in
situ hybridization (FISH) protocols to measure gene expression in 3D, 3) develop an image processing pipeline
to relate gene expression to shear stress, and 4) determine the impact of shear stress on gene expression. Upon
completion, we will have significantly more information on how shear stress affects molecular expression. With
this knowledge, we will be better equipped to determine which molecular pathways are most influenced by altered
hemodynamics, to develop earlier detection methods and pote...

## Key facts

- **NIH application ID:** 10823248
- **Project number:** 5R01HL126747-09
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** MICHAEL W. JENKINS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $743,722
- **Award type:** 5
- **Project period:** 2015-07-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823248

## Citation

> US National Institutes of Health, RePORTER application 10823248, Optical Tools to Assess the Role of Cardiac Function in the Development of Congenital Heart Defects (5R01HL126747-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10823248. Licensed CC0.

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