Asporin, an extracellular protein, regulates cardiac remodeling

项目摘要 细胞外基质（ECM）在心脏重塑过程中改变细胞的反应是至关重要的。最近，I班 富含亮氨酸的小分子蛋白多糖（SLRPs）在缺血性损伤中对心脏功能有巨大影响 或心脏重塑。不良心脏重塑刺激由于TGFβ增加的纤维化瘢痕沉积 对成纤维细胞的活性。在过去的十年中，一种非常规的I类SLRP蛋白asporin（ASPN）已经被发现。 显示在调节TGFβ信号传导和癌症和骨质疏松症中的细胞活力中起作用。生物 ASPN在调节心脏中TGFβ和细胞活力方面的影响尚不清楚。我们的长期目标是解剖 ASPN活性调节的详细机制及其对成纤维细胞和心肌细胞的影响，特别是在 心脏重塑的背景。这些发现将有助于设计有效的基于ASPN的治疗方法， 心衰这项研究的目的是研究ASPN在心肌纤维化和心肌细胞凋亡中的作用。 生存能力。我们的中心假设是ASPN在心脏应激时由成纤维细胞释放并抑制TGFβ 在心脏重塑过程中减少纤维化的信号传导。此外，释放的ASPN作用于心肌细胞， 上调自噬并防止细胞死亡。我们的基本原理是，识别刺激的机制 ASPN在心脏重塑中的保护作用将提供新的治疗机会。该项目将进一步 测试治疗性肽递送以及AAV 9介导ASPN基因的递送在减轻 再灌注损伤和心脏重塑。我们的具体目标将测试以下假设：（目标1）ASPN 抑制纤维化以维持心脏功能并防止不利的心脏重构;（目的2）ASPN诱导 心肌细胞中的自噬;（目的3）ASPN调节缺血情况下的心肌细胞死亡- 再灌注损伤综上所述，我们将更好地了解ASPN在抑制纤维化中的新作用 以及激活自噬以实现有益的心脏重塑。这一贡献意义重大，因为它将建立 ASPN靶向的从ECM到成纤维细胞和心肌细胞的几个途径。此外，当前 虽然有希望限制缺血性损伤，但不能解决不利的心脏重塑的关键问题， 心力衰竭患者中。这项研究具有创新性，因为我们将研究ASPN在 调节纤维化和心肌细胞死亡，这是一个迄今尚未研究的过程。深入了解机制 ASPN活性的增加将为基于ASPN的治疗有益于心脏重塑铺平道路。

Project Summary Extracellular matrix (ECM) is critical during cardiac remodeling in altering the cell’s response. Recently, class I small leucine rich proteoglycans (SLRPs) showed enormous impact on the heart’s function during ischemic injury or cardiac remodeling. Adverse cardiac remodeling stimulates fibrotic scar deposition due to increased TGFβ activity on fibroblasts. In the last decade, a non-conventional class I SLRP protein, asporin (ASPN), has been shown to play a role in regulating TGFβ signaling and cell viability in cancer and osteoporosis. The biological impact of ASPN in regulating TGFβ and cell viability in heart is unknown. Our long-term goal is to dissect the detailed mechanisms regulating ASPN activity and its impact on fibroblasts and cardiomyocytes, particularly in the setting of cardiac remodeling. These discoveries will facilitate design of effective ASPN-based therapies for heart failure. The objective of this grant is to characterize the role of ASPN in fibrosis and cardiomyocyte cell viability. Our central hypothesis is that ASPN is released by fibroblasts during cardiac stress and inhibits TGFβ signaling to reduce fibrosis during cardiac remodeling. Further, released ASPN acts on cardiomyocytes to upregulate autophagy and prevent cell death. Our rationale is that identification of the mechanisms to stimulate ASPN-protective effects in cardiac remodeling will offer new therapeutic opportunities. This project will further test therapeutic peptide delivery as well as AAV9-mediated delivery of ASPN gene for efficacy in mitigating reperfusion injury and cardiac remodeling. Our specific aims will test the following hypotheses: (Aim 1) ASPN inhibits fibrosis to maintain cardiac function and prevents adverse cardiac remodeling; (Aim 2) ASPN induces autophagy in cardiomyocytes; (Aim 3) ASPN regulates cardiomyocyte cell death in the setting of ischemia- reperfusion injury. Upon conclusion, we will better understand the role of novel role of ASPN in inhibiting fibrosis and activating autophagy for beneficial cardiac remodeling. This contribution is significant since it will establish the several pathways targeted by ASPN from ECM to fibroblasts and cardiomyocytes. Furthermore, current therapies, while promising in limiting ischemic injury, fail to address the key issue of adverse cardiac remodeling in heart failure patients. The proposed research is innovative as we will investigate the effects of ASPN in regulating fibrosis and cardiomyocyte cell death, an unexamined process to date. Insight into the mechanisms of ASPN activity will pave the way for ASPN-based therapies to benefit cardiac remodeling.