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Endogenous and exogenous mechanisms that promote myocardial remuscularization in post infarction LV remodeling

Award Number: R01HL114120
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Endogenous and exogenous mechanisms that promote myocardial remuscularization in post infarction LV remodeling Summary / Abstract The molecular and cellular basis for the progressive heart failure is the result of the inability of damaged and apoptotic myocytes to be replaced. While a number of cell- and tissue-based therapies can limit this dysfunction, the proportion of cells that survive at the site of administration for more than a few weeks after transplantation is extremely low. As such, substantial remuscularization of the infarcted region has rarely been reported; and when limited remuscularization has been reported, it is frequently accompanied by potentially lethal ventricular arrhythmias of unknown mechanism. This proposal aims at remuscularization of the injured ventricle from “within” by identifying key regulators of the cell cycle and by promoting the native cardiomyocyte (CM) reenter the cell cycle, and from “outside” by transplanting bioengineered cardiac muscle patch (hCMP) with the key regulators of CM cell cycle upregulated, and with that incorporate a functional vascular network and recapitulate some of the key micro environmental cues of native heart tissue. We recently established a novel hiPSC cell line with MHC-driven overexpression of a key regulator of CM: CCND2 (hiPSC-MHC-CCND2OE), which can remuscularize injured ventricle in rodent model. The central objective of this proposal is to “turn back the clock” of myocyte cell cycle for myocardial repair. The specific Aims ( SA) are: SA1: Identifying the key regulators that promote cell-cycle activity in the hearts of early neonatal pigs after myocardial injury. We will: 1) using state-of-the-art molecular biology and imaging technologies, and the single cell/nucleus RNA sequencing (scRNAseq or snRNAseq) technology to demonstrate these key regulators/signaling pathways that control the myocyte cell cycle; and2) test remuscularization of injured ventricle by manipulating the key regulators using either targeted modRNA or AAV9 to selectively modify these regulators in adult pigs with AMI. SA2a. Engineering hCMPs of previously unattainable size and thickness that are functionally mature and primed for in-vivo vascularization. SA2b. Evaluating the effectiveness of our hCMP constructs for myocardial recovery and remuscularization in a large-animal (swine) model of myocardial injury. We will use state-of-the-art techniques of optical mapping in combination with the 3-dimensional intramural cardiac mapping to delineate potential arrhythmia mechanisms over the entire left-ventricular surface and transmurally.


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: 2023 ( Subtotal = $2,923 )
2023	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	10	7/19/2023	COMPETING CONTINUATION	-$2,360
2023	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	9	11/23/2022	NON-COMPETING CONTINUATION	$5,284
														Subtotal = $2,923

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	002	10	7/29/2022	COMPETING CONTINUATION	$0
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	10	11/29/2021	COMPETING CONTINUATION	$24,948
2022	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	9	11/29/2021	NON-COMPETING CONTINUATION	-$24,948
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $519,750 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	10	6/11/2021	COMPETING CONTINUATION	$519,750
2021	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	9	6/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $519,750

Issue Date FY: 2020 ( Subtotal = $628,744 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	9	4/23/2020	NON-COMPETING CONTINUATION	$628,744
														Subtotal = $628,744

Issue Date FY: 2019 ( Subtotal = $628,744 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	8	5/15/2019	NON-COMPETING CONTINUATION	$628,744
														Subtotal = $628,744

Issue Date FY: 2018 ( Subtotal = $628,744 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	7	5/22/2018	NON-COMPETING CONTINUATION	$628,744
2018	2015	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	5	12/9/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $628,744

Issue Date FY: 2017 ( Subtotal = $646,454 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	6	6/19/2017	COMPETING CONTINUATION	$646,454
														Subtotal = $646,454

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2015	UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	4	11/18/2015	NON-COMPETING CONTINUATION	-$579,957
2016	2015	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	5	11/20/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$579,957
2016	2015	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	352940111	JEFFERSON	USA	Cardiovascular Diseases Research	002	5	8/9/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $644,401 )
2015	2015	UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	4	4/14/2015	NON-COMPETING CONTINUATION	$644,401
														Subtotal = $644,401

Issue Date FY: 2014 ( Subtotal = $641,132 )
2014	2014	UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	3	5/1/2014	NON-COMPETING CONTINUATION	$641,132
														Subtotal = $641,132

Issue Date FY: 2013 ( Subtotal = $622,813 )
2013	2013	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	2	6/10/2013	NON-COMPETING CONTINUATION	$622,813
														Subtotal = $622,813

Issue Date FY: 2012 ( Subtotal = $667,215 )
2012	2012	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	1	8/10/2012	NEW	$667,215
														Subtotal = $667,215

Grand Total All Awards = $5,630,920

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Endogenous and exogenous mechanisms that promote myocardial remuscularization in post infarction LV remodeling

Award Number: R01HL114120

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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