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The role of bioactive lipids in CMC-induced myocardial repair.

生物活性脂质在 CMC 诱导的心肌修复中的作用。

基本信息

批准号：
10593895
负责人：
Marcin Wysoczynski
金额：
$ 38.5万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593895
关键词：
Acute Address Affect Arachidonate 5-Lipoxygenase Cardiac Cardiac Myocytes Catheterization Cell Survival Cell Therapy Cell secretion Cells Cellular Structures Cessation of life Coculture Techniques Data Disease Echocardiography Fibrosis Genes Genetic Heart Heart failure Homeostasis Immune Immune response Immune system Immunohistochemistry Immunosuppression In Vitro Infarction Inflammation Inflammatory Response Injections Kinetics LTB4R gene Left Left Ventricular Function Left ventricular structure Leukotriene B4 Leukotrienes Ligands Link Lipid Synthesis Pathway Lipids Lipoxygenase Macrophage Maps Mass Spectrum Analysis Mediating Mesenchymal Mus Myocardial Myocardial Infarction Myocardium Pathway interactions Phenotype Production Property Prostaglandin-Endoperoxide Synthase Prostaglandins Regulation Research Personnel Role Rupture Severities Sterility Testing Ventricular angiogenesis cyclooxygenase 1 cyclooxygenase 2 genetic manipulation heart function heart preservation immunoregulation improved in vivo in vivo Model insight knock-down lipid metabolism monocyte mouse model novel novel strategies paracrine preservation programs receptor recruit repair function repaired reparative capacity

项目摘要

A variety of sterile diseases, including myocardial infarction (MI) and subsequent repair, involve the immune system. Although unresolved inflammation exacerbates heart failure, depletion of macrophages in the infarcted myocardium leads to left ventricular (LV) rupture and death. Thus, indiscriminate immunosuppression is not a viable approach. Nevertheless, persistent inflammation in the failing heart must be addressed. Unfortunately, significant barriers to progress remain because we do not know how immune cells regulate myocardial repair and what determines their harmful versus salutary actions. Cell therapy provides a unique opportunity for understanding how immune cells contribute to myocardial repair, and recent findings implicate macrophages as direct contributors to cell therapy-mediated myocardial repair. Although few injected cells survive long-term in the recipient, common benefits include reduction of fibrosis, enhanced angiogenesis, and improvement in LV function. These improvements occur independently of differentiation of the injected cells into cardiomyocytes, suggesting that cell therapy must recruit endogenous repair mechanisms; however, these mechanisms remain unidentified. Our preliminary data show that injection of cardiac mesenchymal cells (CMCs) into the infarcted heart promotes accumulation of reparative macrophages, decreases fibrosis, and improves LV function. Co-culture of CMCs with macrophages favors a reparative macrophage program, and it may be due to CMC-derived bioactive lipids—such as prostaglandins, leukotrienes, and resolvins— which offer testable explanations of the `paracrine hypothesis' of cell-mediated repair. Thus, we propose that CMCs recruit monocytes and activate reparative macrophages, which promote favorable anti-fibrotic cardiac remodeling and improve cardiac function in the infarcted heart. In the current project we will determine the capacity for the bioactive lipid synthesis and secretion in CMCs. Mass spectrometry will be performed to explore the role of Cox and Lox pathways in bioactive lipid synthesis in CMCs. Moving forward we will ascertain the role bioactive lipids in macrophage recruitment and their reparative function, with the particular focus on macrophage BLT-1 receptor and its CMC-derived ligands. Finally, we will determine the reparative effect of CMCs with enhanced bioactive lipid synthesis in mouse model of HF. This project will be the first systematic analysis of bioactive lipid synthesis profile in reparative CMCs. This project will provide novel insights into not only pathways of bioactive lipid synthesis in CMC but also the mechanisms regulating cell therapy-mediated myocardial repair.

多种无菌性疾病，包括心肌梗死（MI）和随后的修复，都涉及到