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.

项目摘要心肌梗塞（MI）导致产生大多由心脏外部组织的疤痕矩阵（ECM）。 ECM的降解与沉积之间的平衡是临床的有力预测指标结果。基质金属蛋白酶（MMP）发生ECM降解； ECM存款是由心脏成纤维细胞。 ECM降解和沉积都可以促进广告重塑和进展到内心失败。在MMP家族中，MMP-9据报道是心脏功能障碍的预后指标心肌梗塞（MI）患者；由于MMP-9水平直接与患者死亡率相关。那，优势长期以来，在MI之后抑制MMP-9的抑制作用。但是，使用全局MMP-9抑制进行临床试验由于缺乏MMP抑制剂特异性和MMP-9的重要性，这两者都失败了过程。我们最近确定了ECM衍生的肽（P1159），该肽充当竞争性和特定的MMP-9底物。本文中，我们建议使用P1159调节MI后天然基质的MMP-9裂解。这种方法确实如此不抑制MMP-9活性，使其能够参与基本过程；相反，它调节MMP-9 减少内源性底物的切割的蛋白水解能力，这些底物促进注射和抑制修复。合成肽P1159是MMP-9产生的天然形成的片段C-1158/59的模仿胶原蛋白的裂解。在人类中，内源性C-1158/59的血浆水平与较低左心室填充压力，表明C-1158/59的治疗潜力。确实，用外源治疗的小鼠 P1159 MI显示较少的LV扩张，减少注射和纤维化以及改善心脏功能。体外，我们将整联蛋白α4（ITGA4）鉴定为肽受体。虽然我们知道外源交付是有益的，但 P1159如何调节MI后注射和ECM沉积尚未机械解剖。彼此之间，该提案的中心假设是P1159通过服务后MI后进行不良重塑作为减少促进炎症必要的底物的MMP-9蛋白水解的竞争基材和ECM沉积。阐明由P1159在MI中介导的行动方式和信号通路设置，我们将使用细胞特异性ITGA4转基因动物来识别P1159温度的机制 MI后炎症反应调节心脏成纤维细胞信号传导以减少ECM分泌。和促进巨噬细胞 - 纤维细胞串扰。