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Elucidating the role of Cullin 3 in the heart

Award Number: R01HL173796
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2028

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Elucidating the role of Cullin 3 in the heart - PROJECT SUMMARY Cardiomyocyte (CM) mitochondria play a crucial role in energy production and other essential cellular processes. Disruptions in mitochondrial homeostasis contribute to cardiomyopathies and heart failure, which remain significant global health challenges. Therefore, it is vital to identify novel regulators of mitochondrial homeostasis in the heart to reduce cardiac dysfunction-related mortality. Proper control of mitochondrial biogenesis and turnover is essential for maintaining a healthy mitochondrial population in CMs. Recent research has highlighted the importance of mitochondrial DNA transcription in mitochondrial biogenesis, as well as the role of ubiquitin (Ub) ligase PARKIN in mitophagy. However, there are significant knowledge gaps regarding the upstream signaling involved in mitochondrial DNA transcription and other mitochondrial Ub ligases crucial for mitophagy in CMs. Cullin 3-RING Ub ligase (CRL3) belongs to the multi-subunit Cullin-RING Ub ligases (CRLs) family. In the CRL3 complex, Cullin 3 serves as a scaffold for interacting with the RING-box protein RBX1 and one of the substrate receptors. The assembly of CRL3 requires the conjugation of Cullin 3 by the Ub-like protein NEDD8 (neddylation). Known as a cytosolic Ub ligase, CRL3 controls the degradation of numerous proteins and participates in multiple pathophysiological processes such as organismal development, tumor growth, vascular integrity, and renal sodium transport. Moreover, mutations in Cullin 3 were shown to cause familial hyperkalemic hypertension, autism spectrum disorders, and epilepsy. Despite the increasingly recognized importance of CRL3 in health and disease, its role in mitochondria and the heart remains largely unknown. In silico analyses have revealed an intricate interaction between CRLs and mitochondrial homeostasis. Disturbances in CRLs adversely affect mitochondrial integrity and function in CMs, and depletion of Cullin 3 inhibits mitochondrial turnover and respiration capacity, suggesting a potential role for CRL3 in maintaining mitochondrial homeostasis. Notably, neddylation of Cullin 3 is downregulated during cardiac development but upregulated in human failing hearts and mouse hearts undergoing pathological remodeling. Hence, the goal of this project is to investigate the pathophysiological significance of Cullin 3 in the heart and to elucidate the molecular mechanisms by which Cullin 3 regulates mitochondrial homeostasis using a series of newly generated, genetically engineered mouse models and adenovirus-associated viruses. Three interconnected yet independent aims are proposed: Aim 1 will assess the importance of neddylated Cullin 3 in cardiac maturation and mitochondrial biogenesis, Aim 2 will establish the functional significance of Cullin 3 in mitochondrial turnover in the adult heart, and Aim 3 will investigate the impact of Cullin 3 mutations and deficiency on cardiac remodeling while exploring the potential of targeting Cullin 3 to prevent stress-induced cardiac damage. Successful completion of these experiments will expand and deepen our understanding of how mitochondrial homeostasis is maintained in the developing, homeostatic, and remodeling heart.


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 = $634,044 )
2026	2026	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	3	2/12/2026	NON-COMPETING CONTINUATION	$634,044
														Subtotal = $634,044

Issue Date FY: 2025 ( Subtotal = $667,414 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	2	8/27/2025	NON-COMPETING CONTINUATION	$66,741
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	2/28/2025	NON-COMPETING CONTINUATION	$600,673
														Subtotal = $667,414

Issue Date FY: 2024 ( Subtotal = $667,414 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	2/26/2024	NEW	$600,674
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	1	6/6/2024	NEW	$66,740
														Subtotal = $667,414

Grand Total All Awards = $1,968,872

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Elucidating the role of Cullin 3 in the heart

Award Number: R01HL173796

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2028

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