Regulation of cardiac inflammation by fibroblasts

摘要 心力衰竭是一种进行性疾病，通常因不适当的心脏重塑而加重， 对压力的反应。然而，可以有效靶向纤维化的疗法， 病理性重塑，目前还无法获得。虽然急性损伤后的炎症反应是 对于清除死亡组织至关重要，并且一些纤维化可能是必要的，以保持张力 由于受损心肌的强度，持续的炎症反应可导致不适当的 纤维化程度。几种常驻心脏细胞群与调节心肌细胞的增殖有关。 急性心脏损伤后免疫细胞的组成和活化，但心脏成纤维细胞的作用 在这一过程中，人们知之甚少。这些研究的目的是阐明成纤维细胞在 在调节炎症中发挥作用。我们的初步数据表明，最初的先天免疫 在没有成纤维细胞的情况下，反应正常进行，但炎性细胞群 比存在成纤维细胞时持续更长时间。我们假设Ras信号在心肌细胞中 成纤维细胞在重塑过程中指导抗炎基因表达， 这些途径的相互作用将允许致病性和再生性重塑的分化。在Aim I中， 我们将使用心脏成纤维细胞消融来确定抗炎信号的时间。然后我们将 确定特定的抗炎调节剂。在Aim II中，我们将操纵Ras信号， 成纤维细胞，以确定该途径的改变如何控制炎性细胞浸润，活化， 以及随后的重塑在目标III中，我们将确定这些炎症调节因子是否 在人心脏成纤维细胞中保守。该项目将提供新的见解的作用， 心脏成纤维细胞在心脏损伤后的免疫调节中发挥作用，并识别出 可以在治疗上调节以限制病理性重塑。

Abstract Heart failure is a progressive disease that is often exacerbated by inappropriate cardiac remodeling in response to stress. However, therapies that can efficiently target fibrosis, a key component of pathologic remodeling, are currently unavailable. While an inflammatory response after acute injury is essential for clearing dead tissue, and some fibrosis may be necessary to maintain the tensile strength of injured myocardium, a sustained inflammatory response can lead to inappropriate amounts of fibrosis. Several resident cardiac cell populations have been implicated in regulating the composition and activation of immune cells after acute heart injury, but the role of cardiac fibroblasts in this process is poorly understood. The goal of these studies is to elucidate the role that fibroblasts play in regulating inflammation. Our preliminary data demonstrate that initial innate immune responses proceed normally in the absence of fibroblasts, but populations of inflammatory cells persist longer than when in the presence of fibroblasts. We hypothesize that Ras signaling in cardiac fibroblasts directs anti-inflammatory gene expression later in the remodeling process and identification of these pathways will permit the differentiation of pathogenic and regenerative remodeling. In Aim I, we will use cardiac fibroblast ablation to identify the timing of anti-inflammatory signals. We will then determine the specific anti-inflammatory regulators. In Aim II, we will manipulate Ras signaling in fibroblasts to determine how alteration of this pathway controls inflammatory cell infiltration, activation, and subsequent remodeling. In Aim III, we will determine if these inflammatory regulators are conserved in human cardiac fibroblasts. This project will provide novel insights into the role that cardiac fibroblasts play in immune regulation after cardiac injury, and identify signaling pathways that may be therapeutically modulated to limit pathologic remodeling.