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Cellular and Molecular Mechanisms of the Pathogenesis of Left Ventricular Non-Compaction Cardiomyopathy (LVNC)

Award Number: R01HL121700
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/15/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Cellular and Molecular Mechanisms of the Pathogenesis of Left Ventricular Non-Compaction Cardiomyopathy (LVNC) - Abstract Left ventricular non-compaction (LVNC) is a prevalent pediatric cardiomyopathy characterized by excessive trabeculation and deep intertrabecular recesses (DIR), with mortality rates as high as 47%. Despite its clinical significance, the cellular and molecular mechanisms underlying LVNC remain poorly understood. This proposal aims to elucidate the etiology of LVNC by defining the cellular basis of trabecular non-compaction and hyper-trabeculation, identifying the cellular origins of de novo trabeculation and DIR formation, and determining the role of β- adrenergic receptor (β1/β2AR) signaling in disease progression. Our central hypothesis is that translocation of compact myocardial cells into the trabecular zone drives de novo trabeculation and DIR formation through a β1/β2AR-dependent mechanism. To test this hypothesis, we will use a combination of advanced genetic tools, lineage-tracing strategies, and a newly established isoproterenol (ISO)-induced LVNC mouse model and two genetic LVNC models to test the following three Aims: Aim I: Identify the cellular mechanisms of de novo trabeculation and DIR during LVNC pathogenesis. Aim II: Determine whether and how a subset of CMs in the compact zone contributes to LVNC pathogenesis. Aim III: Investigate how β1&2AR regulate LVNC pathogenesis. We will integrate single-cell RNA sequencing, dual reporter lineage tracing, genetic and pharmacologic interventions to dissect these pathways. These studies will elucidate fundamental mechanisms governing ventricular compaction, providing new insight into the pathogenesis of LVNC. Furthermore, they will evaluate the therapeutic potential of β1AR and β2AR inhibition in the prevention and treatment of LVNC, laying the foundation for targeted interventions in LVNC and related cardiomyopathies.


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: 2026 ( Subtotal = $798,732 )
2026	2026	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Cardiovascular Diseases Research	000	12	8/6/2026	COMPETING CONTINUATION	$798,732
														Subtotal = $798,732

Issue Date FY: 2024 ( Subtotal = $485,779 )
2024	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Cardiovascular Diseases Research	000	11	6/7/2024	NON-COMPETING CONTINUATION	$485,779
														Subtotal = $485,779

Issue Date FY: 2023 ( Subtotal = $506,679 )
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Cardiovascular Diseases Research	000	10	5/27/2023	NON-COMPETING CONTINUATION	$506,679
														Subtotal = $506,679

Issue Date FY: 2022 ( Subtotal = $517,344 )
2022	2022	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Cardiovascular Diseases Research	000	9	7/27/2022	NON-COMPETING CONTINUATION	$517,344
														Subtotal = $517,344

Issue Date FY: 2021 ( Subtotal = $527,702 )
2021	2021	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Cardiovascular Diseases Research	006	8	7/31/2021	NON-COMPETING CONTINUATION	$527,702
2021	2020	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	6	1/31/2021	COMPETING CONTINUATION	-$469,674
2021	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Cardiovascular Diseases Research	001	7	1/31/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$469,674
2021	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Cardiovascular Diseases Research	005	7	6/28/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$56,238
2021	2020	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	003	6	3/2/2021	COMPETING CONTINUATION	$28,303
2021	2020	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	004	6	6/28/2021	COMPETING CONTINUATION	-$56,238
2021	2019	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	002	5	3/2/2021	NON-COMPETING CONTINUATION	-$28,303
														Subtotal = $527,702

Issue Date FY: 2020 ( Subtotal = $569,333 )
2020	2020	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	001	6	5/29/2020	COMPETING CONTINUATION	$569,333
2020	2019	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	5	5/27/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $569,333

Issue Date FY: 2019 ( Subtotal = $395,000 )
2019	2019	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	5	1/12/2019	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2018 ( Subtotal = $395,000 )
2018	2018	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	4	12/5/2017	NON-COMPETING CONTINUATION	$387,100
2018	2018	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	001	4	5/15/2018	NON-COMPETING CONTINUATION	$7,900
														Subtotal = $395,000

Issue Date FY: 2017 ( Subtotal = $395,000 )
2017	2017	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	3	12/2/2016	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2016 ( Subtotal = $395,000 )
2016	2016	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	002	2	2/17/2016	NON-COMPETING CONTINUATION	$5,925
2016	2016	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	2	11/9/2015	NON-COMPETING CONTINUATION	$355,500
2016	2016	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	001	2	11/10/2015	NON-COMPETING CONTINUATION	$33,575
														Subtotal = $395,000

Issue Date FY: 2015 ( Subtotal = $395,000 )
2015	2015	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	1	11/7/2014	NEW	$395,000
														Subtotal = $395,000

Grand Total All Awards = $5,380,569

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Cellular and Molecular Mechanisms of the Pathogenesis of Left Ventricular Non-Compaction Cardiomyopathy (LVNC)

Award Number: R01HL121700

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/15/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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