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不适应。 墙对系统性和局部性因素的反应。在过去的两个资金周期中，我们使用了生物信息学 和系统生物学方法结合体外和体内实验验证来研究细胞 动脉粥样硬化保护和动脉粥样硬化调节血管内皮细胞的分子机制 健康和疾病中的细胞(EC)。我们的结果证明了流量调节的EC表观基因组和 动脉粥样硬化保护表型和倾向于动脉粥样硬化表型的转录本。新出现的证据表明， 动脉粥样硬化的本质与内皮细胞的异质性有关，这是由于内皮细胞固有特性之间的相互作用造成的 和外在剪切力。为了进一步加深我们对EC异构性与 动脉粥样硬化，我们假设介体(例如，MED-1)与谱系依赖的转录相协调 因子(LDTF，如KLF4)和信号依赖转录因子(SDTF，如Smad2)调节 机械转导的时空网络。为检验这一新假设而提出的五个具体目标 目的：1.描述流动介导的EC表观基因组和转录本的时空变化 单细胞分辨；目的2.阐明切应力对内皮细胞和血管间相互作用的影响 具有空间分辨率的平滑肌细胞(SMC)或巨噬细胞(M？S)；目的3.表征 转录本和体内动脉壁调节表观基因组的空间分辨率；目的4.使用 用于构建时间和空间调控的计算和集成数据的系统生物学方法 目的5.用小鼠在疾病水平上验证切应力调节的EC异质性 动脉粥样硬化模型和人类动脉疾病标本。利用多组学平台在单细胞 决议，这项更新建议将破译EC非均质性的剪应力规则和 血管内皮细胞和邻近细胞类型(SMC和M？S)的相应表型变化与 动脉硬化。

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.