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

Award Number: R01HL126747
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2015
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Optical Tools to Assess the Role of Cardiac Function in the Development of Congenital Heart Defects - 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 potentially develop strategies to prevent CHDs more effectively.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $758,901 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	001	10	8/4/2025	NON-COMPETING CONTINUATION	$75,890
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	10	2/14/2025	NON-COMPETING CONTINUATION	$683,011
														Subtotal = $758,901

Issue Date FY: 2024 ( Subtotal = $743,722 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	001	9	6/21/2024	NON-COMPETING CONTINUATION	$60,711
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	9	3/8/2024	NON-COMPETING CONTINUATION	$683,011
														Subtotal = $743,722

Issue Date FY: 2023 ( Subtotal = $779,824 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	8	4/6/2023	NON-COMPETING CONTINUATION	$779,824
														Subtotal = $779,824

Issue Date FY: 2022 ( Subtotal = $774,900 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	001	7	6/18/2022	NON-COMPETING CONTINUATION	$77,492
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	7	3/16/2022	NON-COMPETING CONTINUATION	$697,408
														Subtotal = $774,900

Issue Date FY: 2021 ( Subtotal = $767,418 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	001	6	3/18/2021	COMPETING CONTINUATION	$690,676
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	004	6	7/30/2021	COMPETING CONTINUATION	$129,662
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	002	6	6/23/2021	COMPETING CONTINUATION	$76,742
2021	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	5	3/17/2021	NON-COMPETING CONTINUATION	$0
2021	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	003	5	7/30/2021	NON-COMPETING CONTINUATION	-$129,662
														Subtotal = $767,418

Issue Date FY: 2019 ( Subtotal = $493,857 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	5	6/13/2019	NON-COMPETING CONTINUATION	$493,857
														Subtotal = $493,857

Issue Date FY: 2018 ( Subtotal = $493,857 )
2018	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	4	6/25/2018	NON-COMPETING CONTINUATION	$493,857
														Subtotal = $493,857

Issue Date FY: 2017 ( Subtotal = $538,867 )
2017	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	3	6/19/2017	NON-COMPETING CONTINUATION	$538,867
														Subtotal = $538,867

Issue Date FY: 2016 ( Subtotal = $483,717 )
2016	2016	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	2	6/27/2016	NON-COMPETING CONTINUATION	$483,717
														Subtotal = $483,717

Issue Date FY: 2015 ( Subtotal = $612,717 )
2015	2015	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	1	6/29/2015	NEW	$612,717
														Subtotal = $612,717

Grand Total All Awards = $6,447,780

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

Award Number: R01HL126747

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2015

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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