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Targeting the Sirt-1 pathway to modulate inflammation during murine Kawasaki Disease vasculitis

Award Number: R01HL159297
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Targeting the Sirt-1 pathway to modulate inflammation during murine Kawasaki Disease vasculitis - PROJECT ABSTRACT Kawasaki disease (KD), the leading cause of acquired heart disease among children in the US, is an acute febrile illness and systemic vasculitis believed to be of infectious etiology that causes coronary artery aneurysms and can result in long-term cardiovascular sequelae. Coronary artery aneurysms develop in 25% of untreated KD children, leading to ischemic heart disease and myocardial infarction. While intravenous immunoglobulin (IVIG) treatment lowers this rate to 5%, up to 20% of KD patients are IVIG-resistant and have a greater risk for coronary inflammation. A better understanding of the immune and pathological mechanisms leading to the development of KD vasculitis is needed to identify more efficacious KD therapeutics and prevent the long-term cardiovascular sequelae stemming from tissue inflammation and coronary remodeling. In preliminary studies using a murine model of KD vasculitis, we discovered that genes related to inflammatory responses and IL-1 signaling are upregulated in the inflamed abdominal aorta. In addition, expression of Sirtuin 1 (SIRT1), a histone deacetylase known for its cardioprotective functions, was decreased in the inflamed abdominal aorta of mice during KD vasculitis. Therefore, the central hypothesis of this R01 application is that SIRT1 plays a critical role in preventing bacterial ligand-induced IL-1β-driven vasculitis by promoting autophagy/mitophagy, which impairs NLRP3 inflammasome activation and IL-1β production. To test this hypothesis, we will complete the following specific aims: 1) Determine the expression pattern of SIRT1 and its role in bacterial ligand- induced KD vasculitis and 2) Determine the mechanism by which SIRT1 activity modulates LCWE- induced KD vasculitis. This proposal has a very high translational potential and will determine if compounds known to activate and increase SIRT1 activity will improve or reduce cardiovascular pathology of KD. Importantly, these studies will not only shed light on how SIRT1 influences the inflammatory response during the KD acute phase but will also provide insight into the potential of SIRT1 modulation as a therapeutic intervention to prevent long-term KD cardiovascular complications. Moreover, given the established role of IL-1 signaling in atherosclerosis, our findings may illuminate novel therapeutic directions for a broad range of cardiovascular 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: 2026 ( Subtotal = $0 )
2026	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	2/6/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $417,500 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	6/1/2024	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2023 ( Subtotal = $417,500 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	7/18/2023	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2022 ( Subtotal = $417,500 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	7/1/2022	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2021 ( Subtotal = $417,500 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	6/11/2021	NEW	$417,500
														Subtotal = $417,500

Grand Total All Awards = $1,670,000

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Targeting the Sirt-1 pathway to modulate inflammation during murine Kawasaki Disease vasculitis

Award Number: R01HL159297

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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