Thursday, July 3, 2025 7/3/2025

Role of integrin alpha 5 in the formation of the pharyngeal arch arteries

Award Number: F31HL158065
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 12/18/2024

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Role of integrin alpha 5 in the formation of the pharyngeal arch arteries - PROJECT SUMMARY The aberrant formation of the Pharyngeal Arch Arteries (PAAs) results in severe and lethal forms of congenital heart disease. The PAAs form through vasculogenesis, where an endothelial cell (EC) plexus invades the pharyngeal arches before coalescing into patent PAAs. Our lab has shown that a majority of the ECs that make up the PAAs derives from a population of mesodermal progenitor cells known as the Second Heart Field (SHF). Additionally, our lab has shown that Integrin ɑ5 (Itgɑ5) expression within the Isl1-lineages, encompassing the second heart field and pharyngeal endoderm and ectoderm, regulates the formation of the PAAs through unknown mechanisms. Integrins are cell surface receptors that organize the ECM and relay ECM signals to elicit cellular responses, including cell proliferation, survival, migration, and differentiation. Preliminary data suggests Itgɑ5 regulates the number of SHF-derived ECs that give rise to the PAAs. We hypothesize that integrin ɑ5 expression in the Isl1-lineages regulates the number of SHF-derived ECs in the pharyngeal arches by mediating SHF-progenitor cell survival and/or proliferation, migration, and/or differentiation. In Specific Aim I, we will investigate this hypothesis using Itgɑ5f/- ; Isl1Cre mutant and Itgɑ5f/+ ; Isl1Cre control embryos, which carry the Rosa26nTnG reporter. This reporter marks cells derived from the Isl1-lineages with the expression of nuclear GFP. Utilizing this conditional knockout mouse model and immunohistochemistry, we will investigate the proliferation and apoptosis frequencies, migration patterns, and differentiation capacity, of the Isl1-derived cells that give rise to the ECs of the PAAs. My preliminary data additionally shows SHF-derived ECs crossing the midline in the developing pharyngeal region within our mutants. During vertebrate development, cells in general do not cross the midline ensuring proper left-right patterning. The ECM organization and programmed cell death response at the midline create a barrier that stops cells from migrating across the midline. Because we know Itgɑ5 regulates ECM organization we hypothesize that Itgɑ5 expression in the Isl1-lineages regulates SHF-derived EC patterning through mediating the ECM organization and the programmed cell death response at the midline. We will investigate this hypothesis in Specific Aim II, utilizing our conditional mouse model and immunohistochemistry. We will compare the ECM organization and apoptosis frequency at the midline in control and mutant embryos. Additionally, we will investigate the distribution of Isl1-derived cells at the midline during early embryogenesis because if Isl1-derived cells are able to cross the midline in our mutants, the Isl1-derived cells that give rise to the PAAs could be directed to the wrong side, resulting in aberrant PAA formation. The completion of the experiments outlined in this proposal will provide insights into mechanisms involved in the development of the PAAs and will therefore increase our understanding of how related congenital heart diseases arise, creating new possibilities for the clinical detection, prevention, and treatments of these congenital heart diseases.


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 = -$20,383 )
2025	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	2	1/23/2025	NON-COMPETING CONTINUATION	-$20,383
														Subtotal = -$20,383

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	3	4/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $41,901 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	001	3	3/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$41,901
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	2	3/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $41,901

Issue Date FY: 2022 ( Subtotal = $40,959 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	2	7/5/2022	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	2	5/4/2022	NON-COMPETING CONTINUATION	$40,960
														Subtotal = $40,959

Issue Date FY: 2021 ( Subtotal = $40,243 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	1	2/25/2021	NEW	$40,243
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	1	2/25/2021	NEW	$0
														Subtotal = $40,243

Grand Total All Awards = $102,720

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Role of integrin alpha 5 in the formation of the pharyngeal arch arteries

Award Number: F31HL158065

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 12/18/2024

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