Cell-Cell Interaction in Heart Failure

描述（由申请人提供）：心肌梗死后左心室重塑导致心力衰竭，这是全球死亡的主要原因。导致心力衰竭产生的基本细胞级机制包括肌细胞肥大和凋亡、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。我们最近报道了在小鼠和患者中的一个新观察结果：炎性骨髓细胞（单核细胞、巨噬细胞）不仅侵入急性缺血心肌，而且侵入MI后的远端区域。令人惊讶的是，我们已经检测到他们的存在，在失败的非缺血性心肌梗死后几个月，反映慢性炎症。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中的已知功能将骨髓细胞定位为组织重塑的主管弦乐队，因为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一个原因和新的治疗攻击点。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。我们假设骨髓细胞指示常驻细胞，包括成纤维细胞、肌细胞和内皮细胞具有促炎和促纤维化信号，并且是基质降解蛋白酶的来源。为了研究巡逻，招聘，并在远程心肌实质细胞的白细胞的串扰，我们将遵循免疫细胞的行为，在他们的不受干扰的微环境与体内多通道荧光显微镜的跳动的心脏。从偏远地区分离的细胞的基因表达研究将产生关键信号。我们将使用 体内RNAi疗法敲低循环单核细胞中的CCR2，从而限制它们的募集和单核细胞衍生的巨噬细胞对MI后重塑的有害作用。表型分型将采用活体显微镜、荧光分子断层扫描、电影和标记磁共振成像等多尺度成像。

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.