Systems Biology Analyses for Hemodynamic Regulation of Vascular Homeostasis

血管稳态血流动力学调节的系统生物学分析

基本信息

批准号：
10448495
负责人：
SHU CHIEN
金额：
$ 103.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-24 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10448495
关键词：
Ablation Affect Aorta Arteries Atherosclerosis Bioinformatics Blood Vessels Blood flow Cells Cellular biology Coculture Techniques Consequentialism Data Disease Endothelial Cells Endothelium Enhancers Epigenetic Process Exposure to Functional disorder Funding Gene Expression Genes Health Heterogeneity Homeostasis Human Hyperlipidemia Hypertension In Situ In Vitro Innate Immune Response Knowledge Link MADH2 gene Mediating Mediator of activation protein Modeling Molecular Multiomic Data Mus Nature Pattern Phenotype Prevention Procedures Property Regulation Regulatory Pathway Resolution Role Sampling Series Signal Transduction Smooth Muscle Myocytes Specimen System Systems Biology Technology Testing Time Tissue Sample Transcript Validation Variant Vascular Diseases Vascular Endothelial Cell Vascular Smooth Muscle atheroprotective cardiovascular risk factor cell type cohort epigenome epitranscriptome experience experimental study hemodynamics in silico in vivo macrophage mechanotransduction model development monocyte mouse model multiple omics network models novel promoter response shear stress single-cell RNA sequencing spatiotemporal transcription factor transcriptome

项目摘要

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.

动脉粥样硬化是一种多方面的血管疾病，涉及动脉中多种细胞类型的适应不良在过去的两个融资周期中，我们使用了生物信息学。和系统生物学方法以及体外和体内实验验证来研究细胞以及动脉粥样硬化保护性和动脉粥样硬化易发性流动调节血管内皮细胞的分子机制我们的结果证明了流量调节的 EC 表观基因组和细胞（EC）的关键作用。新出现的证据表明，动脉粥样硬化保护性和动脉粥样硬化倾向表型中的转录组。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在剪切力，以进一步加深我们对 EC 异质性的理解。动脉粥样硬化，我们勇敢地承认介质（例如 MED-1）与谱系依赖性转录相协调因子（LDTF，例如 KLF4）和信号依赖性转录因子（SDTF，例如 SMAD2）来调节为检验这一新假设而提出的五个具体目标。目标 1. 描述流介导的 EC 表观基因组和转录组的时空变化单细胞分辨率；目标 2. 阐明剪切应力对 EC 和血管之间相互作用的影响目标 3. 表征平滑肌细胞 (SMC) 或巨噬细胞 (MØs) 的空间分辨率；具有空间分辨率的体内动脉壁转录组和调节表观基因组；系统生物学方法计算和整合数据以构建时空调节目标 5. 使用小鼠验证疾病水平上剪切应力调节的 EC 异质性利用单细胞多组学平台进行动脉粥样硬化模型和人体动脉疾病标本。决议，本更新提案将破译EC异质性的剪切应力规定和与相关的 EC 和邻近细胞类型（SMC 和 MØ）随之发生的表型变化动脉粥样硬化。