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Targeting FAK-NEDD9 protein-protein interaction to prevent focal adhesion assembly and vascular proliferation in pulmonary arterial hypertension

Award Number: R01HL139613
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Targeting FAK-NEDD9 protein-protein interaction to prevent focal adhesion assembly and vascular proliferation in pulmonary arterial hypertension - Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disease characterized by pulmonary endothelial proliferation, extracellular matrix (ECM) expansion, and interstitial fibrosis that affects distal pulmonary arterioles. Despite the importance of vascular remodeling to morbidity and early mortality in PAH patients, approved pharmacotherapies targeting the molecular events that regulate ECM expansion or angioproliferation do not exist currently. Focal adhesions are multimeric transmembrane complexes that interface endothelial cells with ECM integrins. Focal adhesions drive cellular proliferation and ECM expansion in a process that is initiated by focal adhesion kinase (FAK). Global inhibition of FAK mitigates vascular remodeling and improves PAH in vivo; however, FAK inhibitors are tailored for cancers and associated with off- tissue effects considered particularly high-risk for PAH patients. Thus, developing drugs that prevent focal adhesion assembly in affected tissue selectively is a promising approach to treat PAH. Our laboratory identified Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD9) as a scaffolding protein that regulates vascular fibrosis in PAH. The SH3 domain of NEDD9 is a principal binding target of FAK: formation of the FAK-NEDD9 protein-protein complex regulates focal adhesion signal transduction in numerous cell lines. In the current proposal, we present for the first time the NEDD9-SH3 crystal structure. We synthesized several FAK peptidomimetics (NEDDtides) and demonstrate binding of the NEDDtides to NEDD9 using numerous chemical methods. From the protein structure and novel experimental data, we also identified a reactive thiol residue at Cys18 near the FAK binding groove that is unique to NEDD9. We further show that pulmonary endothelial NEDD9 interacts with the ECM integrin ITGA5 and regulates a key pathway involving the angioproliferation protein VEGF. These observations establish the central hypothesis of the current project: In pulmonary artery endothelial cells, NEDDtide (or analog) inhibits FAK-NEDD9 complex formation to impair focal adhesion assembly. We postulate further that NEDD9-SH3 is a modifiable target by which to inhibit focal adhesion-dependent ECM expansion, VEGF signaling, and, thus, vascular remodeling in PAH. Aim 1 is: Use a structure-guided approach to synthesis and chemical optimization of NEDDtide(s) modified with covalent probe(s) to leverage Cys18 for targeting NEDD9 selectively. We will test binding affinity, potency, and selectivity of NEDDtide(s) using intact mass-spectrometry, fluorescent-based assays and other methods to demonstrate inhibition of focal adhesion by NEDDtide(s) in vitro and in cellulo. Aim 2 is: Use gain- and loss-of-function assays involving mutant NEDD9 constructs and NEDDtide(s) to show that NEDD9-SH3 modulates ITG5A-VEGF signaling at focal adhesions and is a modifiable target by which to inhibit ECM remodeling and angioproliferation in PAH-HPAECs in vitro and experimental PAH in vivo.


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 = $519,022 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Lung Diseases Research	002	7	4/25/2025	NON-COMPETING CONTINUATION	$519,022
2025	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Lung Diseases Research	001	6	2/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$636,832
2025	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	5	2/19/2025	COMPETING CONTINUATION	-$636,832
														Subtotal = $519,022

Issue Date FY: 2024 ( Subtotal = $570,887 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Lung Diseases Research	001	6	5/28/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$570,887
2024	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	5	5/27/2024	COMPETING CONTINUATION	$0
														Subtotal = $570,887

Issue Date FY: 2023 ( Subtotal = $636,832 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	5	6/5/2023	COMPETING CONTINUATION	$636,832
														Subtotal = $636,832

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	4	5/24/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $432,096 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	4	5/15/2021	NON-COMPETING CONTINUATION	$43,211
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	4	1/15/2021	NON-COMPETING CONTINUATION	$388,885
														Subtotal = $432,096

Issue Date FY: 2020 ( Subtotal = $432,096 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	3	1/31/2020	NON-COMPETING CONTINUATION	$21,606
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	3	12/21/2019	NON-COMPETING CONTINUATION	$410,490
														Subtotal = $432,096

Issue Date FY: 2019 ( Subtotal = $435,314 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	2	1/31/2019	NON-COMPETING CONTINUATION	$435,314
														Subtotal = $435,314

Issue Date FY: 2018 ( Subtotal = $448,628 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	1	1/5/2018	NEW	$3,598
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	1	12/22/2017	NEW	$445,030
														Subtotal = $448,628

Grand Total All Awards = $3,474,875

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Targeting FAK-NEDD9 protein-protein interaction to prevent focal adhesion assembly and vascular proliferation in pulmonary arterial hypertension

Award Number: R01HL139613

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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