Mechanisms of ERG in Endothelial Activation

摘要 心血管疾病是全世界最常见的死亡原因， 血管疾病中内皮细胞激活延长，抑制这种激活的分子驱动因素的干预措施， 这一进程将对改善人类健康产生深远影响。尽管如此，治疗方法的发展 为了特异性靶向血管炎症，需要理解驱动这一过程的机制， 暴露于疾病相关条件的细胞中的分子水平。这个应用程序的长期目标是 解构控制人类健康和致病内皮细胞特征的分子机制 细胞，以便这些过程可以用于人类健康。本申请的总体目标是 研究微调内皮特异性转录因子ERG如何操纵的分子属性 内皮细胞基因表达的变化。重要的是，该应用程序结合了 传统的分子方法与基因组学的力量，使有针对性的假设可以测试的 全基因组规模。中心假设是ERG的转录活性对于健康的细胞是必不可少的。 内皮细胞功能和改变其功能的分子相互作用与血管疾病有直接联系。的 中心假设将通过三个具体目标的调查进行检验。第一个将确定具体的 依赖于炎症中存在的上游信号级联的ERG活性的伙伴。第二个将 鉴定ERG的直接转录靶点，使其促炎和抗炎功能永久化。最后 第三个将确定ERG在多大程度上指导两种不同的下游内皮细胞特性， 血流动力学波形，区分体内非活动和激活的血管区域。实验来测试 这些假设将利用人类主动脉内皮细胞来最大化这些发现的可翻译性， 人类遗传学研究和药物开发管道。这种方法是创新的，因为它使用了 基因组学，以测试有针对性的，分子假设，因为它将测试蛋白质之间的新关系， 在血管健康和疾病中还没有被考虑到。这项工作将提供分子 为开发新的干预策略以改善血管健康提供信息的见解， 心血管疾病

ABSTRACT Cardiovascular diseases are the most frequent cause of death worldwide and, given the central role of prolonged endothelial activation in vascular disease, interventions that dampen the molecular drivers of this process would have far-reaching consequences to improve human health. Still, the development of therapies to specifically target vascular inflammation requires that the mechanisms driving this process be understood at the molecular level in cells exposed to disease-relevant conditions. The long-term goal of this application is to deconstruct the molecular mechanisms that govern healthy and pathogenic endothelial cell traits in human cells so that these processes may be exploited for human health. The overall objective of this application is to investigate the molecular attributes that fine-tune how the endothelial-specific transcription factor ERG steers endothelial cell gene expression towards healthy or diseased states. Importantly, this application combines traditional molecular approaches with the power of genomics so that targeted hypotheses may be tested on the genome-wide scale. The central hypothesis is that ERG's transcriptional activity is essential for healthy endothelial cell function, and molecular interactions altering its function are direct links to vascular disease. The central hypothesis will be tested through investigation of three specific aims. The first will identify specific partners of ERG activity that depend on upstream signaling cascades present in inflammation. The second will identify direct transcription targets of ERG that perpetuate its pro- and anti-inflammatory functions. Finally, the third will identify the extent to which ERG directs endothelial cell traits downstream of two different hemodynamic waveforms that distinguish inactive from activated vascular locales in vivo. Experiments to test these hypotheses will utilize human aortic endothelial cells to maximize the translatability of the findings to human genetics research and drug development pipelines. The approach is innovative because it uses genomics to test targeted, molecular hypotheses, and because it will test novel relationships among proteins that have not been considered in vascular health and disease. The proposed work will provide molecular insights to inform the development of novel intervention strategies to improve vascular health and cardiovascular disease.