Systems Biology Analyses for Hemodynamic Regulation of Vascular Homeostasis

动脉粥样硬化是一种多方面的血管疾病，涉及动脉中几种细胞类型的适应不良 应对系统性和局部因素的墙。在过去的两个资助周期中，我们使用生物信息学 和系统生物学方法，以及体外和体内实验验证，以研究细胞 以及动脉粥样硬化保护和动脉粥样硬化酮流动调节血管内皮细胞的分子机制 细胞（EC）在健康和疾病中的作用。我们的研究结果表明，流量调节EC表观基因组的关键作用， 在动脉粥样硬化保护和动脉粥样硬化倾向表型中的转录组。新出现的证据表明， 动脉粥样硬化的性质与EC异质性有关，EC异质性是由EC内在特性之间的相互作用引起的 和外部剪切力。为了进一步加深我们对EC异质性的理解， 动脉粥样硬化，我们假设介质（例如，MED-1）与谱系依赖性转录协调 因素（LDTF，例如，KLF 4）和信号依赖性转录因子（SDTF，例如，SMAD 2）以规管 机械传导的时空网络。为检验这一新假设而提出的五个具体目标 目标：1。为了描述血流介导的EC表观基因组和转录组的时空变化， 单细胞分辨率;目标2.为了阐明切应力对内皮细胞与血管相互作用的影响， 具有空间分辨率的平滑肌细胞（SMC）或巨噬细胞（MCs）;目标3.表征 转录组和调节表观基因组在体内动脉壁的空间分辨率;目的4。雇用 系统生物学方法来计算和整合数据的建设时间和空间的调控 网络;目标5.为了验证剪切应力调节的EC异质性在疾病水平上使用小鼠 动脉粥样硬化模型和人动脉疾病标本。利用多组学平台在单细胞 决议，这一更新建议将破译EC异质性的剪切应力规则和 结果，与以下相关的EC和邻近细胞类型（SMC和MMCs）的表型变化 动脉粥样硬化

Atherosclerosis is a multi-faceted vascular disease that involves maladaptation of several cell types in the arterial wall responding to systemic and local factors. During the last two funding cycles, we have used bioinformatics and system biology approaches together with in vitro and in vivo experimental validations to study the cellular and molecular mechanisms by which atheroprotective and atheroprone flows regulate the vascular endothelial cell (EC) in health and disease. Our results demonstrate the crucial roles of flow-regulated EC epigenomes and transcriptomes in the atheroprotective and athero-prone phenotypes. Emerging evidence suggests that the focal nature of atherosclerosis is linked to EC heterogeneity resulting from interplay between intrinsic EC properties and extrinsic shear forces. To further advance our understanding on EC heterogeneity in relation to atherosclerosis, we hypothesize that mediators (e.g., MED-1) coordinate with lineage-dependent transcription factors (LDTFs, e.g., KLF4) and signal-dependent transcription factors (SDTFs, e.g., SMAD2) to regulate the spatiotemporal networks of mechanotransduction. The five specific aims proposed to test this novel hypothesis are: Aim 1. To delineate the spatiotemporal changes in flow-mediated EC epigenomes and transcriptomes with single-cell resolution; Aim 2. To elucidate the effect of shear stress on interactions between ECs and vascular smooth muscle cells (SMCs) or macrophages (MØs) with spatial resolution; Aim 3. To characterize the transcriptomes and the regulating epigenomes in the arterial wall in vivo with spatial resolution; Aim 4. To employ system biology approaches to compute and integrate data for the construction of temporal and spatial regulatory networks; Aim 5. To validate the shear stress-regulated EC heterogeneity at the disease level using mouse atherosclerosis models and human artery disease specimens. With the use of multi-omics platform at single-cell resolutions, this renewal proposal will decipher the shear stress regulations of the EC heterogeneity and the consequential phenotypical changes of ECs and neighboring cell types (SMCs and MØs) relevant to atherosclerosis.