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Neprilysin mediated phospholamban cleavage in heart failure

Award Number: F30HL179946
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/30/2026
PERIOD OF PERFORMANCE END DATE: 12/29/2027

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Neprilysin mediated phospholamban cleavage in heart failure - PROJECT SUMMARY/ABSTRACT The goal of this three-aim project is to explore downstream consequences of neprilysin cleavage of phospholamban (PLB). Neprilysin is a promiscuous, membrane-bound/circulating metalloprotease which we have shown to be significantly upregulated in heart failure (HF). I have found that neprilysin is able to cleave the C-terminal side of PLB, which may significantly disrupt its ability to regulate the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) in failing hearts and other cardiovascular conditions. My preliminary data suggests that this cleavage can cause significant alterations in PLB membrane anchoring and SR calcium handling. Aim 1 will further investigate how the C-terminal cleavage of PLB will affect its membrane localization and dynamics within the membrane. This aim will also use top down proteomics to understand the specific amino acid location PLB is cleaved, and the amount of neprilysin required for cleavage. Aim 2 seeks to understand how this dysregulation of SERCA will affect important physiological parameters, such as SR calcium handling and [Ca2+]-frequency relationship. These are critical parameters in healthy cardiomyocyte contractility, and important for the heart’s increased contractility in response to a faster heartbeat, which is notably absent in HF. Thus, my experiments to examine how calcium handling is disrupted with neprilysin treatment would prove critical in understanding mechanisms behind alterations in calcium handling in HF using human induced pluripotent stem- cell cardiomyocytes. Finally, Aim 3 seeks to understand the role of neprilysin in human HF, and whether neprilysin inhibitors play a role on PLB cleavage. Using our tissue bank, we can also analyze the portion of patients with arrythmias and whether neprilysin inhibitors had a greater impact on improving mortality and health. Understanding neprilysin’s local actions on PLB cleavage in cardiomyocytes could reveal novel therapeutic strategies for HF and arrhythmias. These proposed experiments will provide critical insights into neprilysin’s role in disease and shift classic paradigms of how neprilysin inhibitors are used to treat HF and arrhythmias.


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 = $36,876 )
2026	2026	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Cardiovascular Diseases Research	000	1	7/6/2026	NEW	$36,876
														Subtotal = $36,876

Grand Total All Awards = $36,876

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Neprilysin mediated phospholamban cleavage in heart failure

Award Number: F30HL179946

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/30/2026

PERIOD OF PERFORMANCE END DATE: 12/29/2027

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