Regulation of TRAF2-Dependent Inflammatory Signaling by Small Proline Rich Protein 1A in the Myocardium

摘要： 心力衰竭(HF)是世界范围内主要的死亡原因，其定义是心脏不能泵出足够的能量。 全身都是血。持续性疾病如高血压或急性高血压可引起心力衰竭。 心肌梗死(MI)等损伤。心肌梗死的特征是冠状动脉血管阻塞。 导致脑缺血。受缺血影响的心肌细胞(CM)发生坏死和凋亡。要清除 由此产生的细胞碎片，免疫细胞渗入该区域，而常驻的成纤维细胞开始分泌 富含细胞外基质的疤痕，维持心脏结构的完整性。这种雄辩的回应是必不可少的。 对于克服最初的伤害，任何特定阶段的夸大都可能产生有害的影响。而当 与高血压和心肌梗塞相关的疾病的病因是独一无二的，它们有相似的特征，如 肥大、炎症和纤维化。为了更好地了解病理性心脏重塑的过程， 我们进行了RNA测序，以确定与病理相关的转录基因表达谱 命运。我们鉴定了一个富含脯氨酸的小蛋白家族(SPRR)，它们在疾病中存在差异调节； 在交界区(BZ)的CFS和CMS中，Sprr1a对炎性细胞因子的反应高度上调 密西西比。初步数据表明，SPRR1A与肿瘤坏死因子(TNF)之间存在一个预测的结合部位 受体相关因子(TRAF)2，一种E3泛素连接酶，作用于 传播炎症信号的质膜。进一步的调查使我们假设 SPRR1A正在改变CMS的泛素化状态或蛋白酶体功能，以阻止促炎信号 并允许炎症消解途径的增加。单独地，SPRR1a和TRAF2可以 也在损伤边缘的细胞存活率中发挥作用。理解中美关系的协调 心肌梗塞后的愈合反应将为进一步的治疗开发奠定基础。这项建议 目的是确定新的体外作用机制和相关的体内并发症与 SPRR1a基因表达的调控。

ABSTRACT: Heart failure (HF) is a leading cause of death worldwide and defined by an inability of the heart to pump sufficient blood throughout the body. HF can be induced by persistent conditions such as high blood pressure, or by acute injuries such as myocardial infarction (MI). MI is characterized by the obstruction of a coronary blood vessel resulting in ischemia. Cardiomyocytes (CMs) affected by the ischemia undergo necrosis and apoptosis. To clear the resulting cellular debris, immune cells infiltrate the area while resident fibroblasts begin to secrete an extracellular matrix-rich scar to maintain the structural integrity of the heart. This eloquent response is essential to overcoming the initial injury, and exaggeration of any particular phase can have detrimental effects. While the etiology of disease associated with high blood pressure and MI are unique, they share similar features such as hypertrophy, inflammation, and fibrosis. To better understand the process of pathological cardiac remodeling, we performed RNA-sequencing to identify transcriptional gene expression profiles associated with pathologic fates. We identified a family of small proline-rich proteins (SPRRs) that are differentially regulated in disease; Sprr1a is highly upregulated in response to inflammatory cytokines in CFs and CMs in the border zone (BZ) after MI. Preliminary data suggests a predicted binding site between SPRR1A and tumor necrosis factor (TNF) receptor associated factor (TRAF)2, an E3 ubiquitin ligase that acts in response to the TNF receptor at the plasma membrane to propagate inflammatory signaling. Further investigation has led us to hypothesize that SPRR1A is altering the ubiquitination status or proteasome function in CMs to halt pro-inflammatory signaling and allow for the increase in inflammation-resolution pathways to occur. Separately, SPRR1A and TRAF2 may also be playing a role in the rate of cell survival along the border of injury. Understanding the coordination of the healing response following MI will build the basis needed for further therapeutic developments. This proposal aims to determine the novel in vitro mechanism of action and associated in vivo complications associated with the modulation of SPRR1A expression.