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Role of fibronectin in the morphogenesis of the cardiac outflow tract

Award Number: R01HL134935
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Role of fibronectin in the morphogenesis of the cardiac outflow tract - PROJECT SUMMARY Congenital heart disease (CHD) is the most common birth defect, affecting approximately 1% of newborns. About 25% of CHD patients require surgery within the first year of life and often need lifelong medical care. Despite advances in surgical care, CHD mortality remains high, highlighting the need for a better understanding of its underlying causes. Abnormal development of the arterial pole of the heart accounts for roughly 30% of CHD cases, leading to severe and often lethal malformations due to the misalignment of the great arteries with the ventricles. The great arteries arise from the cardiac outflow tract (OFT). Initially, the OFT forms as a single vessel connecting the heart with systemic circulation. As the embryo develops, the OFT elongates and becomes subdivided into two vessels, the aorta and pulmonary artery, which then rotate to align with the left and right ventricles, respectively. However, if the OFT fails to elongate during its initial stages of formation, the great arteries fail to properly align with the ventricles, resulting in the mixing of oxygenated and deoxygenated blood after birth. This causes severe morbidity and lethality in the absence of surgical intervention. The OFT elongates via the addition of progenitors from the second heart field (SHF). SHF-derived cells form an epithelial layer in the dorsal pericardial wall (DPW). OFT elongation depends on both tissue tension and epithelial organization in the DPW. When either is altered, SHF cells fail to migrate and incorporate into the OFT, causing defective OFT elongation and, consequently, aberrant great artery morphogenesis. We discovered that the conditional ablation of fibronectin (Fn1) in the cardiogenic mesoderm phenocopies the SHF and OFT abnormalities observed in Tbx1-null mutants, a model of 22q11.2 deletion syndrome—the most prevalent chromosomal disorder in humans. Like Tbx1, Fn1 controls OFT elongation by regulating epithelial organization and mechanotransduction, specifically in the anterior DPW. In this grant application, we propose to determine the mechanisms by which Fn1 regulates epithelial cell shape and mechanotransduction in the SHF. We will test the hypothesis, supported by our preliminary data, that Fn1 regulates SHF cell architecture, biomechanical properties, and OFT elongation by balancing cell- extracellular matrix (ECM) interactions with the anti-adhesive ECM glycoprotein Tenascin C (TnC). We hypothesize that balanced interactions of SHF cells with Fn1 and TnC are required for SHF cells to achieve proper cell shape, size, polarity, and nuclear enrichment of YAP, all of which are necessary for OFT elongation and great artery morphogenesis. Upon completion of these studies, we will gain new insights into the molecular and genetic regulation of OFT elongation and morphogenesis of the arterial pole of the heart. Our research will provide novel candidates (Fn1 and TnC) for prenatal CHD screening and inform targeted therapeutic approaches in the future. Ultimately, understanding how alterations in ECM composition contribute to the pathogenesis of CHD promises to broaden therapeutic strategies and enhance patient outcomes.


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 = $578,421 )
2026	2026	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	5	5/7/2026	COMPETING CONTINUATION	$578,421
														Subtotal = $578,421

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	4	7/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $397,500 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	4	7/9/2020	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2019 ( Subtotal = $397,500 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	002	3	5/16/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$397,500
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	003	3	8/2/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$380,437
2019	2018	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	2	5/14/2019	NON-COMPETING CONTINUATION	-$380,437
2019	2018	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	2	5/11/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $397,500

Issue Date FY: 2018 ( Subtotal = $390,000 )
2018	2018	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	2	5/24/2018	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2017 ( Subtotal = $390,000 )
2017	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	8/7/2017	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $2,153,421

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Role of fibronectin in the morphogenesis of the cardiac outflow tract

Award Number: R01HL134935

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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