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Collagen-derived peptides to target inflammation in myocardial infarction

胶原蛋白衍生肽可靶向心肌梗塞炎症

基本信息

批准号：
10366741
负责人：
Lisandra E de Castro Bras
金额：
$ 37.2万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366741
关键词：
Actins Biological Cardiac Cells Cicatrix Clinical Trials Collagen Congestive Heart Failure Data Deposition Diagnosis Drug or chemical Tissue Distribution Equilibrium Event Extracellular Matrix Extracellular Matrix Degradation Family Fiber Fibroblasts Fibrosis Foundations Gelatinase B Generations Heart failure Human In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Inhibition of Matrix Metalloproteinases Pathway Integrin alpha4 Integrins Knowledge Lead Left Ventricular Remodeling Left ventricular structure Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Molecular Mus Myocardial Myocardial Infarction Myocardial dysfunction Paracrine Communication Pathway interactions Patients Peptide Hydrolases Peptide Receptor Peptides Pharmacology Phase Phenotype Physiology Plasma Process Proteolysis Proteomics Reporting Resolution Role Signal Pathway Signal Transduction Specificity Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Testing Therapeutic Tissues Transgenic Animals cellular targeting heart function improved in vivo inhibitor innovation macrophage mass spectrometric imaging migration mimetics monocyte mortality multiple reaction monitoring neutrophil novel novel therapeutics paracrine polymerization predict clinical outcome preference pressure prognostic indicator receptor repaired response rho GTP-Binding Proteins synthetic peptide

项目摘要

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.

项目总结