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Role of Mitochondrial c-Src in Right Ventricular Dysfunction in Pulmonary Hypertension

Award Number: R01HL169456
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Role of Mitochondrial c-Src in Right Ventricular Dysfunction in Pulmonary Hypertension - Project Summary/Abstract Pulmonary hypertension (PH) is associated with poor prognosis. Right ventricular (RV) dysfunction/failure consequent to high RV afterload is the primary cause of morbidity and mortality in PH, yet no RV targeted therapies are available. This contrasts with several drug classes that are beneficial in LV dysfunction. Therefore, there remains an unmet need to therapeutically target the mechanisms underlying RV dysfunction to improve long-term outcomes in PH. Cardiomyocytes determine RV function in PH. Mitochondria through oxidative phosphorylation (OXPHOS) are the major source of energy in the heart. Targeting RV mitochondrial bioenergetics and function in settings of PH may provide novel therapeutic strategies to improve RV function in PH. Respiratory complexes in the mitochondrial electron transport chain play a critical role in oxidative phosphorylation (OXPHOS) and generation of reactive oxygen species. OXPHOS machinery subunits have been found to be highly phosphorylated, implicating phosphorylation as a means whereby OXPHOS is regulated. To date, tyrosine phosphorylation (P-Tyr) is recognized as a critical regulatory mechanism in mitochondria and c-Src is the major tyrosine kinase localized in mitochondria. The overall goal of this proposal is to delineate the mechanisms underlying impaired RV mitochondrial energetics and function in PH. Our preliminary findings strongly support a novel mechanism governing RV complex I assembly and function in PH that is mediated by P-Tyr of complex proteins. Completion of this study is expected to identify a new targeted strategy to preserve/restore electron transfer chain function in RV cardiomyocytes in vivo in settings of PH.


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 = $394,522 )
2025	2025	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	000	2	2/20/2025	NON-COMPETING CONTINUATION	$394,522
														Subtotal = $394,522

Issue Date FY: 2024 ( Subtotal = $435,362 )
2024	2024	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	001	1	6/26/2024	NEW	$43,537
2024	2024	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	000	1	4/24/2024	NEW	$391,825
														Subtotal = $435,362

Grand Total All Awards = $829,884

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Role of Mitochondrial c-Src in Right Ventricular Dysfunction in Pulmonary Hypertension

Award Number: R01HL169456

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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