The role of PDGF Receptor Signaling in Cardiac Fibroblasts

 描述（由申请人提供）：心脏纤维化是心脏病的主要组成部分，是心脏功能下降的标志。目前，没有直接减弱纤维化的治疗方法。这一主要障碍可以通过靶向常驻成纤维细胞来克服。我们的初步数据表明，PDGFRa信号传导对于维持驻留的心脏成纤维细胞是必要的。本研究的目的是确定成纤维细胞和PDGFR α信号传导在基线和心肌梗死后心脏纤维化中的作用。该提案有两个目标：首先，我们将通过特异性去除心脏成纤维细胞中的PDGFRa表达并确定这些细胞在体内的存活和增殖来定义PDGFRa在成纤维细胞维持中的作用。为了进一步阐明在不存在PDGFRa信号传导的情况下成纤维细胞损失的机制，我们将确定引起这种破坏的细胞功能并检查控制这种功能的信号传导途径。这些信息可以确定控制心脏成纤维细胞数量的机制。我们的第二个目的是研究成纤维细胞在正常心脏功能和损伤后的作用。我们将关注损伤前细胞外基质沉积、心肌细胞和血管的变化。然后，我们将确定成纤维细胞的损失如何影响心脏对心脏损伤的反应， 功能、纤维化面积和心肌细胞肥大作为标志。这些研究的完成将使我们更好地了解成纤维细胞和纤维化的进展， 关于PDGFRa信号传导。

 DESCRIPTION (provided by applicant): Cardiac fibrosis is a major component of heart disease and is a hallmark of decreased cardiac function. Currently, there are no treatments that attenuate fibrosis directly. This major hurdle can be overcome by targeting the resident fibroblast. Our preliminary data indicate that PDGFRa signaling is necessary for the maintenance of the resident cardiac fibroblast. The objective of this study is to determine the role of both the fibroblast and PDGFRa signaling in cardiac fibrobrosis at baseline and after myocardial infarction. This proposal has 2 aims: First, we will define the role of PDGFRa in fibroblast maintenance by specifically removing PDGFRa expression in cardiac fibroblasts and determining the survival and proliferation of these cells in vivo. To further elucidate the mechanism of fibroblast loss in the absence of PDGFRa signaling we will determine the cellular function causing this disruption and examine signaling pathways that control this function. This information could identify mechanisms for controlling cardiac fibroblast numbers. Our second aim is to examine the role of fibroblasts during normal heart function and after injury. We will focus extracellular matrix deposition, cardiomyocyte and vascular alterations before injury. We will then determine how loss of fibroblasts affects the response of the heart to injury using heart function, area of fibrosis, and cardiomyocyte hypertrophy as hallmarks. Completion of these studies will provide a greater understanding of the fibroblast and the progression of fibrosis with regards to PDGFRa signaling.