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Defining New Pathways for Complex Human Heart Failure and Arrhythmia

Award Number: K08HL148701
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/20/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Defining New Pathways for Complex Human Heart Failure and Arrhythmia - Project Summary Normal cardiac function requires synchronization of structural and electrical molecules within the heart. Defects affecting cardiac excitability linked to sudden cardiac death affect ½ million people, and those affecting contractile function, such as in the case of cardiomyopathy, impact another 5.7 million patients in the U.S. each year. However, often overlooked are cardiovascular (CV) phenotypes that result in both electrical and contractile dysfunction. This relationship between contractile and electrical elements is critically important to understand in the patient with congenital heart disease (CHD). There are now more adults (ACHD) living with CHD than children, and in this population the most common late manifestation of CHD is a severely complex phenotype hallmarked by both heart failure and arrhythmia. The ACHD community recognizes the importance of each of these entities, and has set forth high-priority areas of study surrounding heart failure and arrhythmia, with the goal of using models aimed at the ‘cellular keystones underlying CHD’. This proposal embraces that focus, shifting from the study of each of these late CV sequela independently, and taking a broader look at the complex CHD phenotypes that result in both electrical and contractile dysfunction. We have identified a molecule which we believe has both CV electrical and contractile consequences, thereby serving as a good foundational model to study complex phenotypes resulting in combination arrhythmia and heart failure. Ankyrins are a membrane- associated protein directly linked with targeting ion channels in myocytes, neurons and other excitable cells. In heart, ankyrins-B and –G, which function to support myocyte actin/spectrin in the cytoskeleton and function in cellular organization, transport, gating and post-translational modification, are associated with critical membrane ion channels. Canonical AnkG is required for normal NaV1.5 channel targeting in the heart. However, we have identified a novel ‘giant’ cardiac ankyrin-G isoform that we implicate is critical for normal cardiac structure, contractility and electrical conduction. Mice lacking ‘Giant AnkG’ display a dilated and thinned left ventricle with reduced systolic function, consistent with a dilated cardiomyopathy phenotype. These same mice also exhibit electrical dysfunction including ventricular arrhythmia and high-degree heart block. Our new preliminary data support our central hypothesis: A single ankyrin gene produces two separate molecules- each with unique roles in cardiac structural and electrical function. We hypothesize that novel cardiac Giant AnkG functions via a unique sodium-channel independent mechanism leading to regulation myocyte structure, membrane organization and abnormal intra- and inter-cellular signaling. Ultimately, loss of function of this large gene product leads to altered myocardial contraction and defective electrical function.


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 = $160,920 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	5	2/29/2024	NON-COMPETING CONTINUATION	$160,920
														Subtotal = $160,920

Issue Date FY: 2023 ( Subtotal = $160,920 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	4	3/10/2023	NON-COMPETING CONTINUATION	$160,920
														Subtotal = $160,920

Issue Date FY: 2022 ( Subtotal = $160,920 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	001	3	5/4/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$160,920
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	003	3	7/7/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$154,350
2022	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	002	2	7/7/2022	NON-COMPETING CONTINUATION	-$154,350
2022	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	2	5/3/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $160,920

Issue Date FY: 2021 ( Subtotal = $160,920 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	2	3/29/2021	NON-COMPETING CONTINUATION	$160,920
														Subtotal = $160,920

Issue Date FY: 2020 ( Subtotal = $160,920 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	1	4/16/2020	NEW	$160,920
														Subtotal = $160,920

Grand Total All Awards = $804,600

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Defining New Pathways for Complex Human Heart Failure and Arrhythmia

Award Number: K08HL148701

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/20/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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