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Targeting Pannexin 1 as a Novel Mechanism for Arrhythmia and Fibrosis in Duchenne Cardiomyopathy

Award Number: K08HL155852
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/07/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Targeting Pannexin 1 as a Novel Mechanism for Arrhythmia and Fibrosis in Duchenne Cardiomyopathy - PROJECT SUMMARY Cardiovascular disease is the primary cause of death for patients with Duchenne muscular dystrophy (DMD). Arrhythmia and cardiac fibrosis leading to dilated cardiomyopathy are the primary mechanisms of cardiac mortality. Pannexins (Pxs), which are large conductance ion and small molecule channels, have been implicated in other fibroproliferative diseases and are thought to be arrhythmogenic in other model of cardiac disease. Loss of dystrophin, the primary defect in DMD, leads to elevated intracellular calcium (Ca2+) which is also a primary effector of Pxs. The goal of this project is to investigate the mechanisms by which Px1 modulates the development of cardiac fibrosis and arrhythmogenesis in models of DMD cardiomyopathy. Our preliminary data demonstrate a novel role for Px1 in the development of cardiac fibrosis and inducible arrhythmia seen in the D2-mdx model of DMD. Genetic ablation of Px1 in the D2-mdx model (mdxPx1-/-) rescues the cardiac phenotype, including normalization of cardiac fibrosis.as assessed by histopathology and significant reduction in isoproterenol-induced ventricular ectopy. Based on these data, we hypothesize that pathologically elevated intracellular Ca2+, a hallmark of this disease, leads to Px1 activation and results in signaling cascades that activate apoptotic, oxidative, and inflammatory pathways that ultimately lead to fibroblast activation and the development of cardiac fibrosis. We also hypothesize that Px1 channels represent an independent mechanism for ventricular arrhythmia via generation of delayed after-depolarizations (DADs). We with test these hypotheses using the 3 specific aims outlined in this proposal. In Aim 1, we will use transgenic mice with global Px1 deletion in addition to pharmacological Px inhibition to determine if Px1 activation results in triggered arrhythmia. In Aim 2, we will identify the mechanism by which Px1 contributes to cardiac fibrosis in DMD cardiomyopathy using pharmacological and genetic strategies. As Pxs are expressed in both cardiomyocytes and cardiac fibroblasts, Aim 3 will test if fibroblast migration is dependent on Px1 activation in cardiomyocytes and/or fibroblasts using co-culture techniques for human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts. The completion of these studies will help to improve our understanding of the mechanisms of cardiovascular disease in DMD and will provide the basis for further investigation of a novel therapeutic target that has the potential to delay or prevent cardiac mortality in DMD patients. Additionally, this proposal will allow a promising young physician scientist to gain important skill in basic and translational studies in cardiac electrophysiology, cell signaling, and inflammation/fibrosis biology under the expert guidance of a highly accomplished and dedicated mentorship committee. These new skills will provide the foundation for a successful transition from junior investigator to an independently-funded academic physician scientist.


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: 2025 ( Subtotal = $148,052 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	5	1/21/2025	NON-COMPETING CONTINUATION	$148,052
														Subtotal = $148,052

Issue Date FY: 2024 ( Subtotal = $148,214 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	4	11/29/2023	NON-COMPETING CONTINUATION	$148,214
														Subtotal = $148,214

Issue Date FY: 2023 ( Subtotal = $148,405 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	3	12/12/2022	NON-COMPETING CONTINUATION	$148,405
														Subtotal = $148,405

Issue Date FY: 2022 ( Subtotal = $148,560 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	2	12/21/2021	NON-COMPETING CONTINUATION	$148,560
														Subtotal = $148,560

Issue Date FY: 2021 ( Subtotal = $148,714 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	1	1/7/2021	NEW	$148,714
														Subtotal = $148,714

Grand Total All Awards = $741,945

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Targeting Pannexin 1 as a Novel Mechanism for Arrhythmia and Fibrosis in Duchenne Cardiomyopathy

Award Number: K08HL155852

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/07/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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