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Regulation of Fibronectin expression in the neural crest during vascular morphogenesis

Award Number: F31HL151046
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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Regulation of Fibronectin expression in the neural crest during vascular morphogenesis - 7. PROJECT ABSTRACT Congenital heart disease (CHD) is the most common human birth defect, with approximately 40,000 newborns affected annually in the United States. CHD is characterized by any defect in the formation of the heart and is often most severe when involving defects of the aortic arch artery (AAA) vasculature. The AAAs route oxygenated blood from the heart throughout the body and are formed from the remodeling of three pairs of pharyngeal arch arteries (PAAs), namely the 3rd, 4th and 6th. PAA-to-AAA remodeling depends upon a population of stem-like cells known as cardiac neural crest cells (cNCCs), and their differentiation to vascular smooth muscle cells (vSMCs) in the PAAs. Defective cNCC-to-vSMC differentiation results in AAA abnormalities including interrupted aortic arch, a severe defect of the 4th PAA which necessitates surgery upon birth. The extreme nature of arch artery defects resulting from defective cNCC-to-vSMC differentiation presents the need to investigate normal processes of cNCC-to-vSMC differentiation with a particular focus on the sensitivity of the 4th PAA to defects. Our lab previously found that the extracellular matrix protein, Fibronectin (Fn1), is essential for the process of cNCC-to-vSMC differentiation. Fn1 is expressed in cNCCs along a spatiotemporal gradient in murine pharyngeal arches. At E9.5, its expression is detected in migrating cNCCs; but by E10.5, when cNCCs are filling the PAAs, its expression is attenuated. By E11.5, just prior to cNCC-to-vSMC differentiation, its expression is restored in such a manner that cNCCs closest to the PAA lumen exhibit the highest expression while those farther away exhibit less, phenocopying the pattern of cNCC-to-vSMC differentiation. Ablation of Fn1, specifically in cNCCs, results in attenuated vSMC differentiation and defective PAA-to-AAA remodeling. This phenotype is not rescued by exogenous Fn1 or the presence of other matrix proteins, indicating the cell-autonomous function of Fn1 in cNCCs. As critical as Fn1 is in cNCC-to-vSMC differentiation and downstream PAA-to-AAA remodeling, how its expression is regulated in cNCCs is unknown. We hypothesize that the induction of Fn1 within cNCCs is initiated by blood-flow induced TGFβ signaling in cNCCs or the endothelium. We propose to investigate the role of the TGFβ superfamily (via Smad4) in regulating Fn1 in cNCCs for various reasons: (1) The role that the TGFβ family plays in regulating Fn1 during embryogenesis is not well understood (2) TGFβ is a mechanoresponsive pathway which may regulate the spatiotemporal gradient of Fn1 in response to blood flow (3) there is controversy over the role of TGFβ in cNCC development and (4) there are improved genetic tools which will allow us to investigate TGFβ signaling in our system. Our preliminary data suggests that Smad4 is important for cNCC-specific Fn1 production in the pharyngeal arches, yet we do not know the cell type in which Smad4 must function for this response. We propose to address the role of Smad4 in a cell-type specific manner with the experiments outlined in this F31 application (see Research Strategy). Completion of the experiments outlined in this proposal will help to elucidate factors which may contribute to the etiology of arch-artery CHDs.


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: 2024 ( Subtotal = -$27,633 )
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	3	1/29/2024	NON-COMPETING CONTINUATION	-$27,633
														Subtotal = -$27,633

Issue Date FY: 2022 ( Subtotal = $103,785 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	3	7/22/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	3	5/4/2022	NON-COMPETING CONTINUATION	$103,786
														Subtotal = $103,785

Issue Date FY: 2021 ( Subtotal = $103,069 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	2	4/6/2021	NON-COMPETING CONTINUATION	$103,069
														Subtotal = $103,069

Issue Date FY: 2020 ( Subtotal = $102,553 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	003	1	4/13/2020	NEW	$504
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	1	12/23/2019	NEW	$0
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	002	1	2/21/2020	SUPPLEMENT FOR EXPANSION	$62,826
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	1	12/23/2019	NEW	$39,223
														Subtotal = $102,553

Grand Total All Awards = $281,774

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Regulation of Fibronectin expression in the neural crest during vascular morphogenesis

Award Number: F31HL151046

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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