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Collagen-derived peptides to target inflammation in myocardial infarction

Award Number: R01HL152297
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Collagen-derived peptides to target inflammation in myocardial infarction - PROJECT SUMMARY Myocardial infarction (MI) leads to the generation of a scar that is mostly constituted by cardiac extracellular matrix (ECM). The balance between degradation and deposition of ECM is a strong predictor of clinical outcomes. ECM degradation occurs by matrix metalloproteinases (MMPs); and ECM deposition occurs by cardiac fibroblasts. Both ECM degradation and deposition promote adverse remodeling and progression to heart failure. Within the MMP family, MMP-9 has been reported as a prognostic indicator of cardiac dysfunction in myocardial infarction (MI) patients; as MMP-9 levels directly associate with patient mortality. Thus, the advantage of inhibiting MMP-9 after MI has been long recognized. However, clinical trials using global MMP-9 inhibition have mostly failed both due to lack of MMP inhibitor specificity and importance of MMP-9 in several essential processes. We recently identified an ECM-derived peptide (p1159) that acts as a competitive and specific MMP-9 substrate. Herein, we propose use of p1159 to modulate MMP-9 cleavage of native substrates post-MI. This approach does not inhibit MMP-9 activity, allowing it to participate in essential processes; instead, it modulates MMP-9 proteolytic capacity to reduce cleavage of endogenous substrates that promote inflammation and inhibit repair. The synthetic peptide p1159 is a mimetic of the naturally formed fragment C-1158/59 generated by MMP-9 cleavage of collagen post-MI. In humans, plasma levels of endogenous C-1158/59 post-MI correlate with lower left ventricle filling pressure, indicating a therapeutic potential of C-1158/59. Indeed, mice treated with exogenous p1159 post-MI display less LV dilation, reduced inflammation and fibrosis, and improved cardiac function. In vitro, we identified integrin α4 (Itga4) as a peptide receptor. While we know that exogenous delivery is beneficial, how p1159 regulates post-MI inflammation and ECM deposition has not been mechanistically dissected. Accordingly, the central hypothesis of this proposal is that p1159 blunts adverse remodeling after MI by serving as a competitive substrate to reduce MMP-9 proteolysis of substrates necessary for promotion of inflammation and ECM deposition. To elucidate the mode-of-action and signaling pathways mediated by p1159 in the post-MI setting, we will use cell-specific Itga4 transgenic animals to identify the mechanisms whereby p1159 tempers the post-MI inflammatory response, modulates cardiac fibroblast signaling to reduce ECM secretion; and promotes macrophage-fibroblast crosstalk.


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 = $373,834 )
2025	2025	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	4	11/12/2024	NON-COMPETING CONTINUATION	$373,834
														Subtotal = $373,834

Issue Date FY: 2024 ( Subtotal = $373,911 )
2024	2024	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	3	11/6/2023	NON-COMPETING CONTINUATION	$373,911
														Subtotal = $373,911

Issue Date FY: 2023 ( Subtotal = $384,503 )
2023	2023	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	2	11/17/2022	NON-COMPETING CONTINUATION	$332,915
2023	2023	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	001	2	3/6/2023	NON-COMPETING CONTINUATION	$36,991
2023	2022	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	002	1	9/13/2023	NEW	$14,597
														Subtotal = $384,503

Issue Date FY: 2022 ( Subtotal = $372,018 )
2022	2022	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	1	12/14/2021	NEW	$372,018
														Subtotal = $372,018

Grand Total All Awards = $1,504,266

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Collagen-derived peptides to target inflammation in myocardial infarction

Award Number: R01HL152297

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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