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Discovery of small molecule promoters of cardiomyocyte proliferation to restore cardiac performance in disease

Award Number: R01HL148827
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Discovery of small molecule promoters of cardiomyocyte proliferation to restore cardiac performance in disease - TITLE: Discovery of small molecule promoters of cardiomyocyte proliferation to restore cardiac performance in disease PROJECT SUMMARY Cardiovascular disease is the leading cause of mortality in developed and developing nations. Existing CVD pharmacotherapy options do not treat any foundational problems in the myocardium and its constituent cardiomyocytes; rather, unloading the heart and reducing vascular risk factors are the primary therapeutic strategies. Future strategies should move beyond prevention and treatment to restoration, regeneration, and replacement of functional cardiac tissue. Two fundamental challenges face the several mechanisms of potential cardiomyocyte renewal (proliferation of endogenous cardiomyocytes, resident progenitor cells, or extracardiac progenitor cells including bone-marrow derived or pluripotent cells): can a sufficient number of new cardiomyocytes be generated to meaningfully improve cardiac function in various diseases? And since most tissues in adult mammals remain post-mitotic to minimize the risk of cellular transformation into an uncontrolled proliferating neoplastic state, can cardiomyocyte-specific proliferation mechanisms be discovered and manipulated? It is unclear that the reported mechanisms of cardiomyocyte proliferation meet both of these challenges. We have recently developed a novel platform to conduct high throughput screening (HTS) on functional human cardiomyocytes matured from iPS cells. Our innovation is a hypothesis-free, phenotypic screening cascade designed to discover previously unknown, cardiomyocyte selective promoters of cardiomyocyte proliferation. Our hypothesis is this approach will ultimately generation drug-like starting points for future disease-modifying cardiovascular therapeutics. The primary HTS assay has been fully optimized in a 384-well format, and as a demonstration of assay readiness, 12,000 compounds have been screened (Z’- factor of 0.4). Multiple hits from pilot screens were identified and were confirmed and validated in concentration response experiments. A battery of downstream assays has been developed to establish a critical path-testing funnel. Several compounds identified from the pilot screen specifically promoted cardiomyocyte proliferation versus fibroblast proliferation, and furthermore promoted ex vivo proliferation in both neonatal and adult cardiomyocytes isolated from rats. This proposal builds on data from the applicants, an established team from SBP (Drs. Larson and Colas) with basic biology and drug discovery expertise in the field and access to all necessary technologies. The overall goal of this proposal is to generate chemical biology research tools and the starting points for new drugs. As the critical path assays are all in place, we anticipate we can rapidly obtain such probe molecules and start to explore their activity. Our future plans beyond this grant are to ultimately determine their suitability for hit-to-lead activities, begin in vivo evaluation of lead compounds in animal models and eventually patients, and determine their cellular mechanism of action. The product of the work proposed in this application will serve as preliminary data for both hit-to-lead (HTL) grant submissions and parent R01 grant submissions to pursue basic biology understanding of their mechanisms.


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 = -$8,214 )
2024	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	3/6/2024	NON-COMPETING CONTINUATION	-$8,148
2024	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	4	3/6/2024	SUPPLEMENT FOR EXPANSION	-$66
														Subtotal = -$8,214

Issue Date FY: 2023 ( Subtotal = -$41,024 )
2023	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	12/2/2022	SUPPLEMENT FOR EXPANSION	-$41,024
														Subtotal = -$41,024

Issue Date FY: 2022 ( Subtotal = $532,479 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	5/6/2022	NON-COMPETING CONTINUATION	$532,479
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	4	5/17/2022	SUPPLEMENT FOR EXPANSION	$44,979
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	002	4	5/19/2022	NON-COMPETING CONTINUATION	-$44,979
														Subtotal = $532,479

Issue Date FY: 2021 ( Subtotal = $543,920 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	3	4/24/2021	NON-COMPETING CONTINUATION	$487,500
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	003	3	5/12/2021	NON-COMPETING CONTINUATION	$44,979
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	2	2/19/2021	SUPPLEMENT FOR EXPANSION	$11,441
2021	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	002	2	5/12/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $543,920

Issue Date FY: 2020 ( Subtotal = $487,500 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	2	5/12/2020	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2019 ( Subtotal = $487,500 )
2019	2019	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	6/14/2019	NEW	$487,500
														Subtotal = $487,500

Grand Total All Awards = $2,002,161

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Discovery of small molecule promoters of cardiomyocyte proliferation to restore cardiac performance in disease

Award Number: R01HL148827

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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