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

基本信息

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
项目类别：
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

项目摘要

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) 的主要原因全球动脉粥样硬化的发病率和死亡率部分是由炎症引起的异常引起的。内皮细胞 (EC) 的变化，包括屏障功能下降、内皮间质转化和因此，动脉粥样硬化中异常的血管生成是新的治疗靶点。现有的人类单细胞 (sc) RNA 数据集在很大程度上仍未得到表征。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 激活状态然而，这种注释在体内的价值只会与我们解释它们的能力一样强大。因此，所提出的研究将是补充。通过测试假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。 ERG 磷酸化是静态（非激活）生理性血管生成所必需的。在人类晚期动脉粥样硬化病变的最脆弱区域中，血管生成仍然减少这表明炎症诱导的血管生成的发生与 ERG 磷酸化无关。尽管 IL-1b 下游有一个单独的机制，但总体假设是 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，而不是生理性 ERG 磷酸化。该提案的目标是移动。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。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。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。