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，鉴于 血管疾病中长时间的内皮激活，抑制其分子驱动因素的干预措施 这一过程将对改善人类健康产生深远的影响。尽管如此，治疗方法的发展 要特别针对血管炎症，需要了解推动这一过程的机制 暴露在与疾病相关的条件下的细胞的分子水平。此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性的分子机制 细胞，以便这些过程可以为人类健康所利用。此应用程序的总体目标是 研究微调内皮特异性转录因子ERG如何操纵的分子属性 内皮细胞基因在健康或疾病状态下的表达。重要的是，该应用程序结合了 具有基因组学力量的传统分子方法，以便有针对性的假设可以在 全基因组的规模。核心假设是ERG的转录活性对健康是必不可少的 血管内皮细胞的功能以及改变其功能的分子相互作用与血管疾病有直接的联系。这个 中心假说将通过对三个具体目标的调查来检验。第一个将确定具体的 依赖上游信号级联的ERG活动伙伴存在于炎症中。第二个遗嘱 确定ERG的直接转录靶点，以维持其促炎和抗炎功能。最后， 第三，将确定ERG在多大程度上引导内皮细胞特性在两个不同的 血流动力学波形区分活体内非活动和激活的血管部位。要测试的实验 这些假设将利用人的主动脉内皮细胞来最大限度地提高研究结果的可译性 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 基因组学来测试有针对性的分子假说，因为它将测试蛋白质之间的新关系 在血管健康和疾病方面还没有被考虑过。拟议中的工作将提供分子 为开发新的干预策略提供信息以改善血管健康和 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.