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Myocardial Physiology of Growth Differentiation Factor Signaling

Award Number: R01HL169291
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Myocardial Physiology of Growth Differentiation Factor Signaling - SUMMARY: Myocardial Physiology of Growth Differentiation Factor Signaling GDF11 and the closely related protein GDF8 (also known as myostatin) can regulate cardiac hypertrophy. We now have new prospective data in a large cohort of coronary heart disease patients showing that low blood levels of subforms of GDF8 and GDF11 powerfully predict future all-cause mortality. These new data point to specific forms of GDF11 and GDF8 as critical factors in heart disease. Furthermore, human loss- of-function mutations in GDF11 have now been identified that cause multi-system disease, including cardiovascular disease, showing the importance of GDF11 in human biology. GDF11 and GDF8 are members of the transforming growth factor β (TGFβ) superfamily of extracellular ligands and were initially thought to serve similar or redundant roles due to protein sequence identity (90% identical) within their mature signaling domains. We recently collaborated with multiple other laboratories to determine that mature GDF11 is a significantly more potent activator of SMAD2/3 dependent signaling than GDF8 in vitro, likely due to better utilization of key signaling receptors. Moreover, through x-ray crystallography-guided biochemical experiments, we identified key amino acids of the two ligands responsible for their differences in potency. These findings support the concept that GDF11 and GDF8 are likely not functionally equivalent, especially when ligand concentrations are low, as exist in vivo. However, it is not yet understood if differences in GDF11 and GDF8 at the molecular level translate to distinct functional outcomes and pathway activation in vivo. Defining the roles of these ligands in vivo can best be addressed by genetically engineered mice. Using CRISPR technology, we have now generated three new lines of mice with specific changes guided by our structural and biochemical studies on GDF11 vs. GDF8 to address this Project’s three Aims. This project will uncover the biochemistry of these ligands in vivo while retaining regulatory structure of the endogenous genomic loci. Importantly, we have already used Targeted Locus Amplification to prove that we have edited only the intended amino acids in all three of the new lines of mice. Using these newly generated mice, we will pursue the following Aims: Aim 1. To test the hypothesis that introducing the mature domain of GDF11 into the myostatin (GDF8) locus regulates cardiac size and function using Gdf8Gdf11swap mice. Aim 2. To test the hypothesis that gain of potency in GDF8 with two specific amino acids from GDF11 regulates cardiac muscle growth in mice (Gdf8G89D/E91Q mice). Aim 3. To test the hypothesis that GDF11 potency is required to maintain cardiac muscle function in vivo under pressure overload using chimeric mice with specific amino acids from GDF8 introduced into mature GDF11 (Gdf11D89G/Q91E mice).


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 = $608,473 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cardiovascular Diseases Research	000	3	7/10/2025	NON-COMPETING CONTINUATION	$608,473
														Subtotal = $608,473

Issue Date FY: 2024 ( Subtotal = $596,303 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cardiovascular Diseases Research	000	2	5/20/2024	NON-COMPETING CONTINUATION	$596,303
														Subtotal = $596,303

Issue Date FY: 2023 ( Subtotal = $608,473 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cardiovascular Diseases Research	000	1	5/15/2023	NEW	$608,473
														Subtotal = $608,473

Grand Total All Awards = $1,813,249

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Myocardial Physiology of Growth Differentiation Factor Signaling

Award Number: R01HL169291

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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