Cell-Cell Interaction in Heart Failure

心力衰竭中的细胞与细胞相互作用

• 批准号: 8626617
• 负责人: Matthias Nahrendorf
• 金额: $ 43.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626617
• 关键词: Angiotensins; Apoptosis; Atherosclerosis; Attenuated; Autoimmune Diseases; Behavior; Bone Marrow; Candidate Disease Gene; Cardiac; Cause of Death; Cell Adhesion Molecules; Cell Communication; Cells; Chronic; Clinical; Coronary; Data; Dendritic Cells; Digestion; Disease Progression; Endothelial Cells; Evolution; Extracellular Matrix; Extracellular Matrix Degradation; Extramedullary; Fibroblasts; Fibrosis; Flow Cytometry; Fluorescence Microscopy; Gene Expression; Generations; Heart; Heart failure; Hypertrophy; ITGAM gene; Image; Immune; Infarction; Inflammation; Inflammatory; Invaded; Left Ventricular Remodeling; Leukocytes; Ligation; Lymphocyte; Magnetic Resonance Imaging; Measures; Messenger RNA; Molecular; Molecular Profiling; Mus; Muscle Cells; Myeloid Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myofibroblast; Patients; Peptide Hydrolases; Phenotype; Positioning Attribute; Process; Production; RNA Interference; Recruitment Activity; Reporting; Role; Signal Transduction; Site; Small Interfering RNA; Source; Sympathetic Nervous System; Technology; Testing; Therapeutic Effect; Time; Tissues; Ventricular; base; cell behavior; chemokine; chemokine receptor; cytokine; fluorescence molecular tomography; in vivo; intravital microscopy; knock-down; macrophage; molecular pathology; monocyte; nanoparticle; neutrophil; novel; novel therapeutics; progenitor; public health relevance; trafficking

Left ventricular remodeling after myocardial infarction leads to heart failure, a predominant cause of death worldwide. Basic cellular-scale mechanisms contributing to the generation of heart failure include myocyte hypertrophy and apoptosis, heightened protease release leading to extracellular matrix degradation and ventricular dilation, and fibrosis caused by myofibroblasts, among others. We have recently reported a novel observation in mice and patients: inflammatory myeloid cells (monocytes, macrophages) invade not only the acutely ischemic myocardium but also the remote zone after MI. Strikingly, we have detected their presence in failing non-ischemic myocardium months after MI, reflecting chronic inflammation. Their known functions in other chronic inflammatory conditions such as atherosclerosis and autoimmune disease position myeloid cells as master orchestrators of tissue remodeling, as they release pro-inflammatory cytokines, carry a high protease payload, and instigate fibrosis. The role of myeloid cells in the failing myocardium; however, is unknown. Our preliminary data show that macrophages in failing hearts are descendants of inflammatory CCR2+ monocytes, and that their neutralization attenuates post-MI remodeling. We thus hypothesize that myocardial leukocyte presence may reflect a cause -- and new therapeutic point of attack -- for post-MI heart failure. We will study leukocyte's presence, phenotype, subsets and their impact on disease progression. We hypothesize that myeloid cells instruct resident cells, including fibroblasts, myocytes, and endothelial cells with pro-inflammatory and pro-fibrotic signals and are a source of matrix-degrading proteases. To investigate patrolling, recruitment, and cross-talk of leukocytes to parenchymal cells in the remote myocardium, we will follow immune cell's behavior in their undisturbed microenvironment with in vivo multi-channel fluorescence microscopy of the beating heart. Gene expression studies of cells isolated from the remote zone will yield their key signals. We will use in vivo RNAi therapy to knock down CCR2 in circulating monocytes, thus limiting their recruitment and the detrimental effect of monocyte-derived macrophages on post-MI remodeling. Phenotyping will employ multi-scale imaging with intravital microscopy, fluorescence molecular tomography, cine and tagging magnetic resonance imaging.

心肌梗死后左心室重构导致心力衰竭，这是心肌梗死后左心室重构的主要原因。 全球范围内的死因。基本的细胞尺度机制有助于产生 心力衰竭包括肌细胞肥大和凋亡，蛋白酶释放增加导致 细胞外基质降解和心室扩张， 肌成纤维细胞等。我们最近报道了一个新的观察小鼠， 患者：炎性骨髓细胞（单核细胞，巨噬细胞）不仅侵入急性 心肌梗死后的远端区也是如此。令人惊讶的是，我们已经发现了他们的 在MI后几个月出现在衰竭的非缺血性心肌中，反映了慢性炎症。 它们在其他慢性炎症性疾病如动脉粥样硬化和 自身免疫性疾病将髓样细胞定位为组织重塑的主管弦乐队， 它们释放促炎细胞因子、携带高蛋白酶有效载荷并引发纤维化。 然而，髓样细胞在衰竭心肌中的作用尚不清楚。我们的初步数据 显示衰竭心脏中的巨噬细胞是炎症性CCR 2+单核细胞的后代， 并且它们的中和作用减弱了心肌梗死后的重塑。因此，我们假设， 心肌白细胞的存在可能反映了一个原因-和新的治疗攻击点- 心肌梗死后心力衰竭我们将研究白细胞的存在，表型，亚群及其影响 对疾病进展的影响我们假设骨髓细胞指导常驻细胞，包括 具有促炎和促纤维化信号的成纤维细胞、肌细胞和内皮细胞， 是基质降解蛋白酶的来源。查巡、招、串门 白细胞向远端心肌实质细胞的转化，我们将跟踪免疫细胞的 在其未受干扰的微环境中的行为与体内多通道荧光 跳动心脏的显微镜。从偏远地区分离的细胞的基因表达研究 会产生关键信号我们将使用体内RNAi疗法来敲低循环中的CCR 2， 单核细胞，从而限制了它们的募集和单核细胞衍生的 巨噬细胞对心肌梗死后重塑的影响。表型分型将采用多尺度成像， 显微镜、荧光分子断层扫描、电影和标记磁共振成像。