Human endothelial cell heterogeneity and activation in atherosclerosis

摘要 动脉粥样硬化是导致缺血性心脏病(IHD)的主要病理生物学基础 世界范围内的发病率和死亡率。动脉粥样硬化的发生部分是通过炎症诱导的异常 内皮细胞(EC)，包括屏障功能降低，内皮细胞向间充质细胞的转变，以及 异常的血管生成。因此，动脉粥样硬化中的EC状态转换是新的治疗靶点，然而 细胞状态的转变在很大程度上仍未确定。现有的人类单细胞(Sc)RNA数据集 动脉粥样硬化为识别人类新的EC激活状态提供了前所未有的机会 斑块。然而，活体中此类注释的价值将取决于我们解释其 相应的功能状态和潜在机制。因此，拟议的研究将补充 通过测试可能的致动脉粥样硬化的体外EC模型对人类斑块的活体分析 总结在体EC分子特征。此外，内皮限制性转录因子的作用 ERG最近在调节内皮细胞内稳态、细胞激活、血管生成和 发炎。ERG的磷酸化是静止(非激活)生理性血管生成所必需的。然而，ERG 在人类晚期动脉粥样硬化病变中最脆弱的区域，血管生成仍在减少 发生。这表明炎症诱导的血管生成不依赖于ERG的磷酸化 尽管在IL-1b下游有一个单独的机制。最重要的假设是IL-1b诱导 血管生成是人类动脉粥样硬化病变中EC病理生理学的一个标志，而这种血管生成 是由NF-kb介导的，而不是生理性的ERG磷酸化。这项提案的目标是推动 开发识别易受损害的动脉粥样硬化病变的诊断策略，以及 可与现有的脂类方法协同作用，促进血管健康。研究与临床相结合 培训计划将提高申请人的知识和技术、临床和专业技能，并促进 她过渡到下一个职业阶段，成为一名致力于学术医学的富有成效的内科医生和科学家。这个 亚利桑那大学的跨学科关注和协作性质提供了丰富的培训环境 完成拟议的目标并培养申请者的科学生涯。

ABSTRACT Atherosclerosis is the primary pathobiology underlying ischemic heart disease (IHD) which is the leading cause of morbidity and mortality worldwide. Atherosclerosis occurs in-part through inflammation-induced abnormalities of endothelial cells (EC), including decreased barrier function, endothelial-to-mesenchymal transition, and aberrant angiogenesis. EC state transitions in atherosclerosis are thus novel therapeutic targets, however the cell state transitions remain largely uncharacterized. Existing single cell (sc) RNA datasets of human atherosclerosis provide unprecedented opportunity to identify novel EC activation states that populate human plaques. However, the value of such annotations in vivo will only be as powerful as our ability to interpret their corresponding functional states and underlying mechanisms. Therefore, the proposed research will complement in vivo analysis of human plaques by testing the ability of putative pro-atherogenic in vitro EC models to recapitulate in vivo EC molecular signatures. Moreover, a role for the endothelial-restricted transcription factor ERG has recently been clarified in the regulation of endothelial homeostasis, cell activation, angiogenesis, and inflammation. ERG phosphorylation is required for quiescent (non-activated) physiologic angiogenesis. Yet, ERG is diminished in the most vulnerable regions of human advanced atherosclerotic lesions where angiogenesis still occurs. This indicates that inflammation-induced angiogenesis occurs independent of ERG phosphorylation though a separate mechanism downstream of IL-1b. The overarching hypothesis is that IL-1b-induced angiogenesis is a hallmark of EC pathophysiology in human atherosclerotic lesions and that this angiogenesis is mediated by NF-kb, rather than physiological ERG phosphorylation. The goal of this proposal is to move toward development of diagnostic strategies identifying vulnerable atherosclerotic lesions, and therapies that may act in synergy with existing lipid approaches to promote vascular health. The integrated research and clinical training plan will enhance the applicant’s knowledge and technical, clinical, and professional skills, and facilitate her transition to the next career stage as a productive physician-scientist dedicated to academic medicine. The interdisciplinary focus and collaborative nature of the University of Arizona provides a rich training environment to complete the proposed aims and nurture the applicant’s scientific career.