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Scalable platform for optimizing human cardiac tissue engineering via optical pacing and on-demand oxygenation

Award Number: R01HL144157
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) are emerging as an invaluable in vitro human experimental platform for disease modeling, drug discovery, cardiotoxicity screening, gene editing and functional genomics. For the first time, cardiac electrophysiology has access to a scalable human experimental model, which, currently, offers the only path to personalized (cardiac) medicine as patient-derived iPS-CMs can be generated on a progressively faster time scale. The clear potential of this technology motivates efforts to address the main criticisms facing iPS-CMs, namely the need for further maturation and reduction of phenotype heterogeneity. As multiple approaches are being pursued to improve iPS-CM maturation and to approximate the functionality of the adult human myocardium, we argue that combinatorial optimizations necessitate new high-throughput (HT) technology and automation. The overall goal of this project is to develop and validate a scalable platform for optimizing cardiac tissue engineering via chronic reconfigurable optical pacing and “on-demand” oxygenation for gaining mechanistic insights into cardiac metabolism and electrophysiology, a platform we call ChROME. Chronic electrical stimulation is a viable lead to iPS-CM maturation, yet it has remained under-explored, specifically as related to the role of mass transport and oxygenation during such stimulation. Leveraging our expertise in the theoretical and experimental use of optogenetic tools for cardiac applications (Entcheva) and automation (Kostov, Li, Entcheva, Kay), we propose to design and validate the first-generation HT-ChROME platform, that will integrate continuous monitoring of key physiological parameters. Our team’s expertise in optical oxygen sensing (Kostov), in-house manufacturing of “on-demand” oxygenation nanocarriers (perfluorocarbons, PFC) (Kay) and metabolic characterization (Kay, Beard) will be applied to address the increased metabolic demands during stimulation. The ability to quantify “functional maturation” by relevant measures (voltage, calcium, contraction) in a high-throughput manner (Entcheva) in 2D and 3D cardiac tissue constructs (Vunjak-Novakovic), using our automated platform OptoDyCE (all-optical dynamic cardiac electrophysiology) is critical in this undertaking. Employing these HT tools and other imaging and omics modalities (Popratiloff, Horvath), we will elucidate the spectrum of responses triggered by chronic stimulation of iPS-CMs: beneficial/maturation effects vs. pathological overload effects, depending on load and oxygenation conditions. The proposed HT-ChROME platform represents a critical step in resolving issues impeding progress with iPS-CMs to accelerate their wide-spread adoption in basic and translational applications. The obtained large-scale data will inform a new generation of biophysical models linking human cardiac metabolism and electrophysiology.


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 = $0 )
2024	2022	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	4	11/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $673,613 )
2022	2022	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	001	4	6/13/2022	NON-COMPETING CONTINUATION	$67,362
2022	2022	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	4	1/31/2022	NON-COMPETING CONTINUATION	$606,251
														Subtotal = $673,613

Issue Date FY: 2021 ( Subtotal = $690,516 )
2021	2021	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	3	1/19/2021	NON-COMPETING CONTINUATION	$621,465
2021	2021	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	001	3	8/17/2021	NON-COMPETING CONTINUATION	$69,051
														Subtotal = $690,516

Issue Date FY: 2020 ( Subtotal = $706,471 )
2020	2020	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	2	1/31/2020	NON-COMPETING CONTINUATION	$706,471
														Subtotal = $706,471

Issue Date FY: 2019 ( Subtotal = $728,876 )
2019	2019	THE GEORGE WASHINGTON UNIVERSITY	2121 I ST NW STE 601	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	1	12/17/2018	NEW	$728,876
														Subtotal = $728,876

Grand Total All Awards = $2,799,476

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Scalable platform for optimizing human cardiac tissue engineering via optical pacing and on-demand oxygenation

Award Number: R01HL144157

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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