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.
We propose to use the systems biology approach combining in vitro, in vivo, and in silico experimental procedures, as well as human vessel specimens, to elucidate the epigenetic mechanisms of hemodynamic regulation of endothelium. The resultant mechanistic and regulatory network models will provide critical information on vascular biology in normal and pathophysiological conditions. The study will also provide novel knowledge for disease prevention, treatments, and management.
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