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Cell-Cell Interaction in Heart Failure

心力衰竭中的细胞与细胞相互作用

基本信息

批准号：
8996193
负责人：
Matthias Nahrendorf
金额：
$ 43.02万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/8996193
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 Health 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 RNA Interference Therapy 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 trafficking

项目摘要

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：心肌梗死后左室重构导致心力衰竭，这是世界范围内的主要死亡原因。导致心力衰竭的基本细胞级机制包括心肌细胞肥大和凋亡、导致细胞外基质降解和心室扩张的蛋白酶释放增加，以及肌成纤维细胞引起的纤维化等。我们最近在小鼠和患者身上报道了一项新的观察：炎性髓系细胞(单核细胞、巨噬细胞)不仅侵袭急性缺血的心肌，而且还侵袭MI后的远区。引人注目的是，我们在心肌梗塞后几个月的衰竭非缺血型心肌中检测到它们的存在，反映了慢性炎症。它们在其他慢性炎症条件下的已知功能，如动脉粥样硬化和自身免疫性疾病，使髓系细胞成为组织重塑的主要协调者，因为它们释放促炎细胞因子，携带高蛋白水解酶负载，并引发纤维化。髓系细胞在衰竭心肌中的作用；然而，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性CCR2+单核细胞的后代，它们的中和作用减弱了MI后的重塑。因此，我们假设心肌白细胞的存在可能反映了心肌梗死后心力衰竭的病因和新的治疗要点。我们将研究白细胞的存在、表型、亚群及其对疾病进展的影响。我们假设髓系细胞指示包括成纤维细胞、肌细胞和内皮细胞在内的常驻细胞具有促炎和促纤维化信号，并且是基质降解蛋白水解酶的来源。为了研究远端心肌中白细胞对实质细胞的巡视、募集和相互作用，我们将利用活体心脏跳动的多通道荧光显微镜来跟踪免疫细胞在其未受干扰的微环境中的行为。从偏远地区分离的细胞的基因表达研究将得出它们的关键信号。我们将使用体内RNAi治疗可以抑制循环单核细胞中的CCR2，从而限制其募集和单核细胞来源的巨噬细胞对心肌梗死后重塑的不利影响。表型鉴定将采用多尺度成像，包括活体显微镜、荧光分子断层成像、电影和标记磁共振成像。