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Calcium/ Calmodulin Activated Kinases in Smooth Muscle

Award Number: R56HL049426
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/1994
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Calcium/ Calmodulin Activated Kinases in Smooth Muscle - Project Summary: This ongoing research project is aimed at defining functions of multi-functional serine/threonine Ca2+/Calmodulin-dependent protein kinase II (CaMKII) isozymes in injury- and disease- induced vascular remodeling. CaMKII is structurally complex and is expressed as a large hetero-multimeric holoenzyme with 12-14 individual kinase subunits. CAMK2 genes undergo extensive alternative splicing to produce variants that can affect holoenzyme subcellular localization and protein interactions. The central hypothesis is that cell-specific expression and activation of CaMKII isoforms and splice variants are functional determinants of integrated vascular remodeling in response to injury and disease. The first specific aim extends our expertise in CaMKII structure and function in vascular smooth muscle to the vascular endothelium, in the context of an in vivo mouse model of intraluminal arterial injury that simulates aspects of in-stent restenosis. The functions of vascular endothelial cell CaMKII isoforms in re- endothelialization following intraluminal injury are tested by conditional knockout of specific Camk2 genes in genetically engineered mice. Regulation of the CaMKII isoform by STAT3 and the role of CaMKII in mediating STAT3-dependent functions are tested in this inflammatory environment. The second specific aim capitalizes on knowledge of CaMKII variant expression in vascular smooth muscle and tests the functional significance of an alternatively spliced c-terminal amino acid sequence in CaMKIIthat mediates formation of a CaMKII/Fyn complex, and subsequent regulation of cellular processes involved in vascular smooth muscle cell motility and proliferation A novel CaMKII antisense exon-skipping oligonucleotide (ESO) approach, designed to precisely interfere with expression of this sequence has been validated in vitro. ESOs will be administered to mice prior to intraluminal arterial injury with the goal of limiting vascular smooth muscle migration to the intima and subsequent neointimal hyperplasia, without affecting vasculoprotective endothelial regeneration. The final aim investigates the function of CaMKII isoforms in promoting programmed cell death by necroptosis in vascular smooth muscle and the role of this mechanism is promoting progression of abdominal aortic aneurysm. This aim is carried out in collaboration with labs at Augusta University and the University of Wisconsin and is investigated using mouse models of aortic aneurysm and conditional knockout of specific Camk2 genes in vascular smooth muscle. Relevance: Accomplishing these aims will provide detailed information on the functional importance of specific CaMKII isoform variants in vascular injury, in stent-restenosis and aneurysmal disease. Application of antisense ESOs targeting CaMKII may provide novel therapeutic approaches to mitigate progression of vascular disease.


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	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	25	3/20/2026	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	25	9/5/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $582,904 )
2022	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	25	9/22/2022	COMPETING CONTINUATION	$582,904
														Subtotal = $582,904

Issue Date FY: 2009 ( Subtotal = $0 )
2009	2008	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	16	4/16/2009	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $392,500 )
2008	2008	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Cardiovascular Diseases Research	000	16	8/8/2008	COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Grand Total All Awards = $975,404

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Calcium/ Calmodulin Activated Kinases in Smooth Muscle

Award Number: R56HL049426

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/1994

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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