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：
9403707
负责人：
SHU CHIEN
金额：
$ 105.76万
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 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9403707
关键词：
Arteries Atherosclerosis Biology Blood Vessels Cell physiology Cellular biology Characteristics Chromatin Chromatin Structure Clinical Medicine Computer Simulation DNA DNA Methylation Data Disease Endothelial Cells Endothelium Epigenetic Process Event Functional disorder Gene Expression Genetic Genetic Transcription Goals Grant Health Homeostasis Human In Vitro Investigation Knowledge Lead Maps Measurement Mediating Methods Modeling Modification Molecular Molecular Profiling Mus Network-based Pattern Pharmacology Phenotype Physiological Play Procedures Regulation Regulator Genes Regulatory Pathway Research Role Series Signal Transduction Specimen System Systems Biology Technology Testing Time Transcriptional Regulation Translations Trees Untranslated RNA Validation Variant Vascular Endothelial Cell atheroprotective base chromatin immunoprecipitation chromatin modification chromatin remodeling data integration disease phenotype disorder prevention epigenetic regulation genome-wide hemodynamics histone modification human subject human tissue in vivo loss of function mechanotransduction multi-scale modeling network models novel reconstruction response shear stress time interval transcriptome transcriptome sequencing

项目摘要

Hemodynamic regulation is important in endothelium homeostasis. In our first four years of this systems biology grant, we established the signaling and transcription mechanisms of endothelial cell response to atheroprotective and atheroprone shear stresses in vitro and in vivo. We have continued to develop the first dynamical model of EC transcriptome regulated by different shear stresses with an extensive time-series study. Through which, we have established the significant role of epigenetic modifications, particularly chromatin remodeling, in EC transcriptome regulations. These findings lead us to hypothesize that atheroprotective and atheroprone flows induce differential changes in histone modifications and long-range DNA interactions mediated by long non-coding RNA (lncRNA) to lead to distinct transcriptome underlying endothelial homeostasis vs. dysfunction. We further hypothesize that these changes are dynamically regulated to result in distinct temporal signals and gene expression. We propose to study the temporal delineation of the sequence of events in which signaling leads to chromatin modifications and long-range DNA interaction followed by transcription, thus causing further translational and post-transcriptional responses, and eventually normal vs. diseased phenotype. The proposed research will serve as the first multiscale systems study of endothelial response to shear stress to elucidate the physiological and pathophysiological mechanisms important for the onset and progression of atherosclerotic diseases. Our goal is to explore the epigenetic regulation of transcription in mechanistic details, and the specific objectives include the following: 1) measurement and identification of epigenetic and regulatory factors that differentially regulate EC function under different shearing conditions (ChIP-seq method), 2) study of chromatin structure and topology on EC function under shear flows (4C method), 3) integrative analysis of epigenetic and transcriptional data to provide mechanisms and build dynamical regulatory networks of shear-mediated phenotypes in EC (systems biology methods), and 4) testing and validation of novel hypotheses of hemodynamic regulation in vitro, in silico and in vivo using genetic and pharmacological perturbation methods, including studies on normal and diseased artery tissues from human subjects. We anticipate that the results from this project will provide a comprehensive multiscale model of flow-mediated functional consequences in ECs for normal and pathophysiology.

血流动力学调节在内皮稳态中很重要。在我们使用这个系统的头四年里生物学资助，我们建立了内皮细胞响应的信号传导和转录机制体外和体内的动脉粥样硬化保护和动脉粥样硬化易发剪切应力。我们继续开发第一个具有广泛时间序列的不同剪切应力调节的 EC 转录组动力学模型学习。通过它，我们确定了表观遗传修饰的重要作用，特别是 EC 转录组法规中的染色质重塑。这些发现使我们推测动脉粥样硬化保护性和动脉粥样硬化易发性流动诱导组蛋白修饰和长程的差异变化由长非编码 RNA (lncRNA) 介导的 DNA 相互作用导致不同的转录组内皮稳态与功能障碍。我们进一步假设这些变化是动态调节的产生不同的时间信号和基因表达。我们建议研究一下时间划分信号传导导致染色质修饰和长程 DNA 相互作用的事件序列随后进行转录，从而引起进一步的翻译和转录后反应，最终正常表型与患病表型。拟议的研究将作为第一个多尺度系统研究内皮对剪切应力的反应以阐明生理和病理生理机制对于动脉粥样硬化疾病的发生和进展具有重要意义。我们的目标是探索表观遗传学转录调控的机制细节，具体目标包括以下内容：1）测量和鉴定差异调节 EC 功能的表观遗传和调节因素不同剪切条件下（ChIP-seq方法），2）EC上染色质结构和拓扑的研究剪切流下的功能（4C 方法），3) 表观遗传和转录数据的综合分析，以提供机制并建立 EC 中剪切介导表型的动态调控网络（系统生物学方法），以及4）体外、计算机和体内血流动力学调节新假设的测试和验证使用遗传和药理学扰动方法进行体内研究，包括对正常和患病动脉的研究来自人类受试者的组织。我们预计该项目的结果将提供全面的 EC 中流介导的功能后果对正常和病理生理学的多尺度模型。