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Microphysiological Model of Human Cardiac Sympathetic Innervation

Award Number: R01HL164936
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Microphysiological Model of Human Cardiac Sympathetic Innervation - PROJECT SUMMARY Goal: We will develop and validate a microphysiological platform of human cardiac sympathetic innervation for in vitro modeling of the human cardiac sympathetic innervation and apply autonomic neuron specification and its interaction with a fatal cardiac disease. The heart is heavily innervated by the autonomic nervous system that consists of both parasympathetic and sympathetic nerves, providing feedback control and regulate overall cardiac performance. Historically, the development of new therapeutic agents targeting cardiac neuropathies have utilized animal models, which exhibited various limitations due to the disparity in homeostatic mechanisms of autonomic nervous systems and the inability to recapitulate accurate human disease phenotypes. In our proposed work, we will develop a novel compartmentalized 3D microelectrode array (MEA) co-culture platform to model human sympathetic innervation and address the fundamental questions on sympatho-cardiac connections, reciprocal regulation, and development of cardiac and autonomic cells. Furthermore, with arrhythmogenic cardiomyopathy (ACM) patient-derived human induced pluripotent stem cells (hiPSC), we expect to recapitulate ACM syndromic phenotypes and examine the diseased cardiac sympathetic innervation on our microphysiological platform, conducive to understanding neuromodulation as well as the neuronal contribution to heart function and disease. We will leverage state-of-art techniques developed by our team: (1) high-throughput multimodal 3D microelectrode arrays, (2) single-cell transcriptomes from human autonomic neurons and cardiac cells for a continuum of molecular changes during their interactions, (3) genetic reporter systems with isogenic control cells to define specific human autonomic neuron populations and perform high- resolution analysis of the neuron-cardiac connection, (4) the optogenetic control of neuronal activities on connected cardiac tissue. Focus/Aim: Our proposed research focuses on developing an in vitro platform to study neuro-cardiac interactions with hiPSCs. We will develop and optimize a compartmentalized 3D MEA co- culture platform in multi-well format to monitor electrophysiology properties of cardiomyocytes, sympathetic neurons and neuro-cardiac junction, followed by evaluation of the platform’s ability to support functional synapse formation with optogenetic neuronal stimulation (Aim 1). We will also generate the developmental trajectory of hiPSC-cardiomyocytes connected to hiPSC-sympathetic neurons through single cell transcriptomic analysis, as well as structural and functional changes in hiPSC-CMs following neuronal stimulations (Aim 2). Furthermore, we will examine whether the innervation affects cell fate choice (Aim 2). In Aim 3, we will employ ACM patient- derived hiPSC/hESCs harboring desmosomal gene mutations onto our microphysiological platform and investigate the role of sympathetic innervation in pathogenic phenotypes presented by ACM, which will be validated in vivo. The proposed in vitro model of cardiac autonomic innervation could provide broad applications, including preclinical drug testing and in vitro disease modeling for etiological understanding of cardiac autonomic cardiomyopathies and neuropathies.


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 = $694,482 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	001	4	8/15/2025	NON-COMPETING CONTINUATION	$694,482
2025	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	3	6/5/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $694,482

Issue Date FY: 2024 ( Subtotal = $765,057 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	3	6/27/2024	NON-COMPETING CONTINUATION	$690,903
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	001	3	7/1/2024	SUPPLEMENT FOR EXPANSION	$74,154
														Subtotal = $765,057

Issue Date FY: 2023 ( Subtotal = $963,667 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	12/5/2022	SUPPLEMENT FOR EXPANSION	$44,348
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	003	2	6/27/2023	SUPPLEMENT FOR EXPANSION	$54,173
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	001	1	12/6/2022	SUPPLEMENT FOR EXPANSION	$75,437
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	004	2	6/28/2023	SUPPLEMENT FOR EXPANSION	$74,154
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	002	2	6/25/2023	NON-COMPETING CONTINUATION	$715,555
														Subtotal = $963,667

Issue Date FY: 2022 ( Subtotal = $741,815 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	6/6/2022	NEW	$741,815
														Subtotal = $741,815

Grand Total All Awards = $3,165,021

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Microphysiological Model of Human Cardiac Sympathetic Innervation

Award Number: R01HL164936

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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