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ERK1/2-Integrin Signaling in Desmosome-Dyad Crosstalk

Award Number: R01HL157741
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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ERK1/2-Integrin Signaling in Desmosome-Dyad Crosstalk - PROJECT SUMMARY Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited disease characterized by fibro-fatty infiltration of the heart, life-threatening ventricular arrhythmias and sudden cardiac death, particularly in response to sympathetic stress. ARVC is a leading cause of sudden cardiac death among young athletes with no prior symptoms or diagnosis of cardiovascular disease. Desmosome cell-adhesion gene mutations constitute the majority of familial ARVC cases, but it remains largely unknown how catecholamine-sensitive ventricular tachycardia and cardiac remodeling processes are facilitated by desmosome dysfunction. Patient management is therefore limited to improving quality of life by reducing arrhythmic symptoms or cardiac transplantation upon advanced heart failure. To begin to uncover mechanisms inherent to ARVC, we performed unbiased mass spectrometry analysis of ventricular samples from patients with different desmosomal gene mutations. Our preliminary data demonstrate that integrin β1D is significantly downregulated in ARVC resulting in de- stabilization of RyR2 ryanodine receptor Ca2+ channels that localize to cardiac dyad junctions. Mechanistically, we find that ERK1/2 activation in response to desmosome loss results in ubiquitin-dependent degradation of integrin β1D, RyR2 Ser-2030 phosphorylation, sarcoplasmic reticulum Ca2+ leak and arrhythmogenesis. Importantly, hearts of our integrin β1D knockout mice exhibit ARVC-like disease with increased RyR2 phosphorylation, catecholamine-induced ventricular arrhythmias and cardiac fibrosis. We hypothesize that communication between desmosome junctions and cardiac dyads is essential for maintaining Ca2+ homeostasis and that ERK1/2 activation-induced loss of integrin β1D impairs this “desmosome-dyad crosstalk” thereby promoting RyR2-dependent and catecholamine-sensitive arrhythmogenesis and fibrotic infiltration in ARVC. We further hypothesize that interventions targeting this pathway may offer a promising approach for treating ARVC. To test our hypothesis, we have generated three congenic knock-in mouse models using CRISPR-Cas9 that contain mutations equivalent to those we identified from human ARVC patients. In Aim 1, we will determine the pathogenicity of knock-in ARVC mutations in recapitulating cardiac remodeling, catecholamine-induced arrhythmogenesis and desmosome-dyad crosstalk in mutant ARVC mice. In Aims 2 and 3, we will test whether mutation-induced ARVC phenotypes can be effectively prevented through ERK1/2 (Aim 2) and RyR2 (Aim 3) inhibition. We expect our studies to show that life-threatening ventricular arrhythmias and heart failure from ARVC can be therapeutically managed by modulating desmosome-dyad crosstalk and attenuating Ca2+ handling dysfunction.


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: 2024 ( Subtotal = $608,195 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	4	8/7/2024	NON-COMPETING CONTINUATION	$608,195
														Subtotal = $608,195

Issue Date FY: 2023 ( Subtotal = $620,608 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	3	8/16/2023	NON-COMPETING CONTINUATION	$620,608
														Subtotal = $620,608

Issue Date FY: 2022 ( Subtotal = $620,608 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	001	2	8/19/2022	NON-COMPETING CONTINUATION	$620,608
2022	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	1	3/25/2022	NEW	$0
														Subtotal = $620,608

Issue Date FY: 2021 ( Subtotal = $620,608 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	1	9/1/2021	NEW	$620,608
														Subtotal = $620,608

Grand Total All Awards = $2,470,019

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ERK1/2-Integrin Signaling in Desmosome-Dyad Crosstalk

Award Number: R01HL157741

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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