Human endothelial cell heterogeneity and activation in atherosclerosis

动脉粥样硬化中的人内皮细胞异质性和激活

• 批准号: 10707010
• 负责人: Maria Adelus
• 金额: $ 4.24万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-26 至 2024-08-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10707010
• 关键词: 3-Dimensional; Abnormal Endothelial Cell; Angiogenesis Inhibition; Angiogenic Switch; Aorta; Arizona; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; Cardiovascular system; Cell Line; Cell model; Cells; Clinical; Complement; Data; Data Set; Dedications; Development; Disease; Endothelial Cells; Endothelium; Environment; Event; Experimental Models; Extracellular Matrix; Functional disorder; Gene Expression; Genes; Goals; Health; Heterogeneity; Homeostasis; Human; Human Genome; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Knowledge; Length; Lipids; Measurement; Measures; Mediating; Medicine; Mesenchymal; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Myocardial Ischemia; NF-kappa B; Nature; Nuclear; Phosphorylation; Physicians; Physiologic Neovascularization; Physiological; Productivity; Public Health; RNA; Regulation; Research; Research Training; Risk; Role; Rupture; Scientist; Signal Transduction; Small Interfering RNA; Testing; Training; Translations; Tube; Universities; angiogenesis; antagonist; candidate validation; career; clinical training; cytokine; diagnostic strategy; experimental study; in vitro Model; in vivo; knock-down; mortality; mutant; new therapeutic target; novel; pharmacologic; primary outcome; programs; secondary outcome; single-cell RNA sequencing; skills; synergism; transcription factor; transcriptome; transcriptomics

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.

抽象的 动脉粥样硬化是导致缺血性心脏病 (IHD) 的主要原因 全球发病率和死亡率。动脉粥样硬化部分是通过炎症引起的异常发生的 内皮细胞 (EC) 的变化，包括屏障功能下降、内皮间质转化和 异常的血管生成。因此，动脉粥样硬化中的 EC 状态转变是新的治疗靶点，然而 细胞状态转变在很大程度上仍然未知。现有的人类单细胞 (sc) RNA 数据集 动脉粥样硬化提供了前所未有的机会来识别人类中新的 EC 激活状态 牌匾。然而，此类注释在体内的价值只会与我们解释其注释的能力一样强大。 相应的功能状态和底层机制。因此，拟议的研究将补充 通过测试推定的促动脉粥样硬化体外 EC 模型的能力，对人体斑块进行体内分析 概括体内 EC 分子特征。此外，内皮限制转录因子的作用 最近，ERG 在内皮稳态、细胞活化、血管生成和血管生成的调节中得到了阐明。 炎。 ERG 磷酸化是静态（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的最脆弱区域中，血管生成仍然减少 发生。这表明炎症诱导的血管生成的发生独立于 ERG 磷酸化 通过 IL-1b 下游的单独机制。总体假设是 IL-1b 诱导的 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，并且这种血管生成 是由 NF-kb 介导的，而不是生理 ERG 磷酸化。该提案的目标是推动 致力于开发识别脆弱动脉粥样硬化病变的诊断策略和治疗方法 可能与现有的脂质方法协同作用，以促进血管健康。综合研究与临床 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 她作为一名致力于学术医学的多产医师科学家过渡到下一个职业阶段。这 亚利桑那大学的跨学科重点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人的科学事业。