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: 10534283
• 负责人: Maria Adelus
• 金额: $ 4.15万
• 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/10534283
• 关键词: 3-Dimensional; Abnormal Endothelial Cell; Angiogenesis Inhibition; Angiogenic Switch; Arizona; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; Cardiovascular system; Cell Line; Cell model; Cells; Clinical; Complement; Data; Data Set; 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; Lead; Length; Lipids; Measurement; Measures; Mediating; Medicine; Mesenchymal; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Myocardial Ischemia; NF-kappa B; Nature; Nuclear; Pharmacology; Phosphorylation; Physicians; Physiologic Neovascularization; Physiological; Public Health; RNA; Regulation; Research; Risk; Role; Rupture; Scientist; Signal Transduction; Small Interfering RNA; Testing; Training; Translations; Tube; Universities; activating transcription factor; angiogenesis; antagonist; career; cytokine; diagnostic strategy; experimental study; in vitro Model; in vivo; knock-down; mortality; mutant; new therapeutic target; novel; 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.

摘要 动脉粥样硬化是缺血性心脏病（IHD）的主要病理基础， 的发病率和死亡率。动脉粥样硬化的发生部分是由于炎症引起的异常 内皮细胞（EC），包括屏障功能降低，内皮细胞向间充质转化， 异常血管生成因此，动脉粥样硬化中的EC状态转变是新的治疗靶点，然而， 细胞状态转变仍然很大程度上未被表征。现有的人类单细胞（sc）RNA数据集 动脉粥样硬化为识别人类中新型EC激活状态提供了前所未有的机会 斑块然而，这种注释在体内的价值将只与我们解释它们的能力一样强大。 相应的功能状态和潜在机制。因此，拟议的研究将补充 通过测试推定的促动脉粥样硬化体外EC模型的能力， 概括体内EC分子特征。此外，内皮限制性转录因子 最近已经阐明ERG在调节内皮稳态、细胞活化、血管生成和血管生成中的作用。 炎症ERG磷酸化是静止（非活化）生理性血管生成所需的。然而，ERG 在人类晚期动脉粥样硬化病变的最脆弱区域， 发生。这表明炎症诱导的血管生成不依赖于ERG磷酸化 虽然在IL-1b下游有一个单独的机制。总体假设是IL-1b诱导的 血管生成是人动脉粥样硬化病变中EC病理生理学的标志， 是由NF-kb介导的，而不是生理性ERG磷酸化。这项提案的目的是 致力于开发识别易损动脉粥样硬化病变的诊断策略，以及 可以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 她过渡到下一个职业阶段，作为一个富有成效的医生，科学家致力于学术医学。的 跨学科的重点和亚利桑那大学的协作性质提供了丰富的培训环境 以完成建议的目标和培养申请人的科学事业。