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Ubiquitination and Endothelial Fibrosis in Early Pulmonary Arterial Hypertension

Award Number: K08HL151976
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Ubiquitination and Endothelial Fibrosis in Early Pulmonary Arterial Hypertension - PROJECT SUMMARY/ABSTRACT This K08 Mentored Clinical Scientist Research Career Development Award describes a five-year research and training program to establish the principal investigator (PI) as an independent, R01-funded physician-scientist in the field of pulmonary vascular medicine. Co-mentorship by Bradley Maron, M.D., an expert in cysteinyl thiol biochemistry, vascular fibrosis, and PAH pathobiology and pathophysiology, and Joseph Loscalzo, M.D., Ph.D., an expert in redox biochemistry, network medicine, and proteomics, will oversee the PI’s research and professional development activities at Brigham and Women’s Hospital and Harvard Medical School. Scientific publication, guidance from an advisory committee, didactic education, and presentation at scientific conferences will support the scientific aims of the project and provide career development in three key training areas: the pathobiology of PAH inception, kinase ubiquitination, and experimental PAH models. The PI is guaranteed >80% protected academic time to dedicate to the proposed K08 program. PAH is characterized by endothelial dysfunction and oxidant stress that promotes fibrotic remodeling of the pulmonary arterioles, leading to right heart failure, and death. Mortality and hospitalization increase incrementally beginning at a mean pulmonary artery pressure (mPAP) below values that were previously thought to be pathogenic. Therefore, treatment of early-stage PAH may improve clinical outcome, but effective therapies do not exist because the pathobiology of endothelial dysfunction and vascular remodeling in early PAH is not known. We provide novel data that early-stage PAH is characterized by pulmonary arteriolar fibrosis, impaired right ventricle-pulmonary artery (RV-PA) coupling, and increased endothelial C-terminal src kinase (Csk) expression occurring prior to the development of elevated mPAP in vivo. Computational modeling predicts that the Csk binding-partner and E3 ubiquitin ligase Casitas b-lineage proto-oncogene (Cbl) is susceptible to oxidative modification at cysteinyl thiol 396 (Cys396). We hypothesize that oxidation of endothelial Cbl-Cys396 prevents Csk ubiquitination to increase Csk-dependent fibrosis and impair RV-PA coupling in early-stage PAH. To test this hypothesis, we propose the following specific aims: 1) Determine the impact of Cbl-Cys396 oxidation on Csk ubiquitination and expression in cultured human PAECs, 2) Assess the role of increased endothelial Csk on fibrillar collagen expression in cultured human PAECs, and 3) Test the effect of Csk inhibition on RV-PA coupling in early- and advanced-stage PAH in vivo. We anticipate that findings from this K08 will establish Csk- targeted therapy as a novel strategy by which to prevent or reverse endothelial fibrosis and vascular remodeling prior to the development of elevated mPAP and right heart failure in PAH. Furthermore, this research program will establish kinase-ubiquitin ligase dysregulation in early-stage PAH as a plane of separation from the PI’s current co-mentors.


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 = -$1,572 )
2026	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	5	12/18/2025	NON-COMPETING CONTINUATION	-$1,572
														Subtotal = -$1,572

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	5	1/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $168,952 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	5	7/2/2024	NON-COMPETING CONTINUATION	$168,952
														Subtotal = $168,952

Issue Date FY: 2023 ( Subtotal = $168,952 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	4	5/16/2023	NON-COMPETING CONTINUATION	$168,952
														Subtotal = $168,952

Issue Date FY: 2022 ( Subtotal = $168,952 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	3	6/13/2022	NON-COMPETING CONTINUATION	$168,952
														Subtotal = $168,952

Issue Date FY: 2021 ( Subtotal = $168,859 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	2	7/20/2021	NON-COMPETING CONTINUATION	$168,859
														Subtotal = $168,859

Issue Date FY: 2020 ( Subtotal = $168,696 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	1	7/1/2020	NEW	$168,696
														Subtotal = $168,696

Grand Total All Awards = $842,839

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Ubiquitination and Endothelial Fibrosis in Early Pulmonary Arterial Hypertension

Award Number: K08HL151976

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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