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Novel role for the spectrin cytoskeleton in regulation of cardiac fibroblast activity, long-range communication and injury-induced fibrosis

Award Number: R01HL171689
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Novel role for the spectrin cytoskeleton in regulation of cardiac fibroblast activity, long-range communication and injury-induced fibrosis - Project Summary/Abstract Myocardial infarction (MI) is a major cause of death and disability worldwide, affecting >800,000 Americans annually. A delicate balance of repair and remodeling processes is required to preserve the structural integrity and reinforce the injured myocardium following MI. Cardiac fibroblasts (CFs) are among the most numerous cell types in the heart and play an essential role in fibrotic remodeling. Following ischemic injury, surviving CFs exhibit a highly dynamic response involving the transition into an activated phenotype characterized by increased proliferation, migration to the infarct region, and secretion of fibrotic proteins. Further, CFs secrete a battery of paracrine signals to help coordinate the organ-level response to injury. Thus, proper healing requires dynamic spatial and temporal control over CF function. Dysregulation of the CF response to injury promotes pathological fibrosis, increased risk for arrhythmia, and cardiac dysfunction. While there have been many studies exploring the diverse signaling cascades and stressors that cause CF activation, the precise molecular pathways responsible for orchestrating dynamic changes in CF function across spatial and temporal scales are not well understood. Spectrin proteins are important for providing structural membrane support and spatiotemporal regulation for cell signaling events. Recent work identified stress-induced loss of βIV-spectrin, to be an important step in CF activation and fibrosis. Further, loss of βIV-spectrin was found to depend on Ca2+/calmodulin-dependent protein kinase II (CaMKII). A broader role has been identified for βIV-spectrin/CaMKII in regulating CF gene expression through an interaction with signal transducer and activation of transcription 3 (STAT3), a signaling molecule and transcription factor that promotes profibrotic mechanisms. Specifically, CaMKII is activated and promotes loss of βIV-spectrin and redistribution of STAT3 to the nucleus that lead to changes in fibrotic gene expression. Further, we identified a molecular switch for βIV-spectrin stability involving direct phosphorylation by calmodulin- dependent protein kinase II (CaMKII). Together these data support our central hypothesis that βIV-spectrin coordinates a tunable network for temporal and spatial control of CF function and the normal healing process following MI. These studies seek to offer new mechanistic insight into how the myocardial repair process is orchestrated and to improve therapeutic options for patients who have experienced MI.


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 = $539,968 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	3	3/18/2026	NON-COMPETING CONTINUATION	$16,529
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	3	2/16/2026	NON-COMPETING CONTINUATION	$523,439
														Subtotal = $539,968

Issue Date FY: 2025 ( Subtotal = $550,988 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	2	8/27/2025	NON-COMPETING CONTINUATION	$55,099
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	2	11/8/2024	NON-COMPETING CONTINUATION	$495,889
														Subtotal = $550,988

Issue Date FY: 2024 ( Subtotal = $550,988 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	1	6/7/2024	NEW	$55,100
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	1	12/1/2023	NEW	$495,888
														Subtotal = $550,988

Grand Total All Awards = $1,641,944

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Novel role for the spectrin cytoskeleton in regulation of cardiac fibroblast activity, long-range communication and injury-induced fibrosis

Award Number: R01HL171689

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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