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Determining the regulatory role of microprotein ALN on SERCA2a and heart contractility

Award Number: F30HL172585
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/15/2025
PERIOD OF PERFORMANCE END DATE: 01/02/2027

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Determining the regulatory role of microprotein ALN on SERCA2a and heart contractility - Project Summary/Abstract Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Cardiomyocyte calcium (Ca2+) dysregulation is a central feature of disease and is largely driven by defects in the activity of a critical Ca2+ pump called the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a). SERCA2a itself is dynamically regulated by the small protein phospholamban (PLN), which inhibits SERCA2a via direct binding and reducing its Ca2+ affinity. Heart disease is associated with SERCA2a/PLN dysfunction, which further worsens Ca2+ disequilibrium and disease progression. However, our knowledge of Ca2+ regulation in the heart remains incomplete, therefore few advances have been made to restore cardiomyocyte Ca2+ homeostasis in disease conditions. Our lab recently discovered the microprotein another-regulin (ALN) as a SERCA2a-inhibiting microprotein that is enriched in cardiomyocytes. My preliminary data indicates that the activity of ALN may be controlled by phosphorylation on position Serine19, whereby in vitro co-immunoprecipitation experiments in HEK293 cells show that this phosphorylation event results in the dissociation of ALN from SERCA2a. Studies in isolated adult mouse cardiomyocytes stimulated with various G-protein-coupled receptor agonists indicate that ALN is phosphorylated downstream of Gq activation, thus presenting ALN as a novel regulator of Ca2+ in the heart. This preliminary evidence has led to our central hypothesis that ALN uniquely integrates neuroendocrine signaling in cardiomyocytes via SERCA2a regulation of Ca2+ signaling and heart contractility. This proposal will test this hypothesis by determining how ALN phosphorylation affects ALN-SERCA2a binding affinity and SERCA2a enzymatic activity (Aim 1). This proposal also explores neuroendocrine and Gq pathway activation upstream of ALN phosphorylation and its resulting regulation of SERCA2a activity (Aim 2). The completion of this proposal will lead to advances in our knowledge of cardiomyocyte Ca2+ handling and Ca2+ dysregulation that occurs during disease. Such findings may lead to the development of novel therapeutics aimed at restoring Ca2+ homeostasis, an area which is currently lacking in cardiovascular care. The Aims herein expect to show that phosphorylation of ALN on Serine19 downstream of Gq signaling causes its dissociation from SERCA2a and relief of its inhibitory effects, thus resulting in increased cardiomyocyte Ca2+ cycling and contractility. The trainee leading this proposed project is currently a second-year graduate MD/PhD student at Cincinnati Children’s Hospital Medical Center in the laboratory of Dr. Cat Makarewich. The candidate will use this proposal to gain meaningful experience in conducting cardiovascular research, leading to a strong base of knowledge for the treatment and prevention of chronic cardiovascular 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 = $54,538 )
2026	2026	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	001	2	3/25/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$54,538
2026	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	1	3/24/2026	NEW	$0
														Subtotal = $54,538

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	1	9/24/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $41,915 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	001	1	8/28/2024	NEW	$0
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	1	8/28/2024	NEW	$41,915
														Subtotal = $41,915

Grand Total All Awards = $96,453

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Determining the regulatory role of microprotein ALN on SERCA2a and heart contractility

Award Number: F30HL172585

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/15/2025

PERIOD OF PERFORMANCE END DATE: 01/02/2027

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