Integration of single-cell imaging and multi-omics sequencing to study EC mechano-pathophysiology

整合单细胞成像和多组学测序来研究 EC 机械病理生理学

基本信息

  • 批准号:
    10825307
  • 负责人:
  • 金额:
    $ 62.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-05-01 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Summary Epigenetic regulation of vascular functions has been found to play crucial roles in cardiovascular diseases. Vascular endothelial cells (ECs), which are exposed to different flow patterns, regulate vascular homeostasis. Differential epigenetic changes, e.g. histone modifications, caused by different flow patterns regulate EC gene expression profile and hence functional consequences. The coupling of histone phosphorylation, methylation, and acetylation have recently been identified to regulate gene expressions through the distinct chromatin remodeling complexes, which would alter the consequential phenotypic outcome. However, there is a paucity of study in the flow-regulation of histone modifications in vascular cells. We hypothesize that the coupling among epigenetic histone phosphorylation, methylation, and acetylation may serve as a transducing mechanism to regulate EC gene expressions under different patterns of flows. We will develop a directed evolution strategy for the systematic optimization and tuning of FRET biosensors with distinct colors to simultaneously monitor different histone modifications with high sensitivity and specificity. These biosensors will be used to track multiple histone modifications simultaneously in the same live cell and unravel the evolving multiplex landscape of histone modifications under different flows. We will further employ the endonuclease-deficient Cas9 (dCas9), small guide RNAs (sgRNAs) and split FPs to track the dynamics of histone modifications at the specific loci of EC phenotype marker genes. Our epigenetic manipulation system will then be employed to modulate epigenetics at these specific loci and determine their effects on gene expressions and consequent cellular functions in single live cells under different flows. The identified epigenetic profiles will then be modulated in vivo, and the consequent gene expression and phenotypic outcome examined. Four specific aims are proposed: 1) Develop and optimize FRET biosensors to visualize the dynamic histone modifications in single cells, 2) Unravel the spatiotemporal coupling of histone phosphorylation-methylation-acetylation in regulating EC functions under different flows, 3) Establish the roles of locus-specific histone modifications in regulating EC gene expression under flows, 4) Elucidate the effect of histone modifications on gene expression and lesion formation in vivo. The simultaneous tracking of the spatiotemporal dynamics of histone modifications in the nucleus in conjunction with cell proliferation and inflammation in a single live cell will allow the elucidation of the spatiotemporal transducing mechanism in regulating epigenetic modulations and pathophysiological consequences upon the exposure of ECs to hemodynamic cues. The mechanistic insights obtained should allow us to identify the potential molecular targets and facilitate the design of pharmaceutical interventions for pathologic processes. As such, the project should have transformative impact in the field of vascular mechanobiology, particularly related to the molecular regulations of cell cycle and inflammation in mediating the development of atherosclerosis.
总结

项目成果

期刊论文数量(65)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
FRET imaging of calcium signaling in live cells in the microenvironment.
微环境中活细胞中钙信号传导的 FRET 成像。
Control of the activity of CAR-T cells within tumours via focused ultrasound.
Tracking the Dynamic Histone Methylation of H3K27 in Live Cancer Cells.
跟踪活癌细胞中H3K27的动态组蛋白甲基化。
  • DOI:
    10.1021/acssensors.1c01670
  • 发表时间:
    2021-12-24
  • 期刊:
  • 影响因子:
    8.9
  • 作者:
    Gong, Ya;Wei, Chujun;Cheng, Leonardo;Ma, Fengyi;Lu, Shaoying;Peng, Qin;Liu, Longwei;Wang, Yingxiao
  • 通讯作者:
    Wang, Yingxiao
Electroporation-delivered fluorescent protein biosensors for probing molecular activities in cells without genetic encoding.
电穿孔的荧光蛋白生物传感器,用于探测无基因编码的细胞中的分子活性。
Visualizing Spatiotemporal Dynamics of Intercellular Mechanotransmission upon Wounding.
  • DOI:
    10.1021/acsphotonics.8b00383
  • 发表时间:
    2018-08
  • 期刊:
  • 影响因子:
    7
  • 作者:
    Pengzhi Wang;Jing Liang;Linda Z. Shi;Yi Wang;Ping Zhang;Mingxing Ouyang;D. Preece;Qin Peng;Lunan Shao;Jason Fan;Jie Sun;Shawn S. Li;M. Berns;Huimin Zhao;Yingxiao Wang
  • 通讯作者:
    Pengzhi Wang;Jing Liang;Linda Z. Shi;Yi Wang;Ping Zhang;Mingxing Ouyang;D. Preece;Qin Peng;Lunan Shao;Jason Fan;Jie Sun;Shawn S. Li;M. Berns;Huimin Zhao;Yingxiao Wang
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SHU CHIEN其他文献

SHU CHIEN的其他文献

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{{ truncateString('SHU CHIEN', 18)}}的其他基金

Locus-specific Imaging of Dynamic Histone Methylations during Reprogramming
重编程过程中动态组蛋白甲基化的位点特异性成像
  • 批准号:
    9922921
  • 财政年份:
    2017
  • 资助金额:
    $ 62.38万
  • 项目类别:
The Organizational Hub and Web Portal for the 4D Nucleome Network
4D 核组网络的组织中心和门户网站
  • 批准号:
    9344559
  • 财政年份:
    2015
  • 资助金额:
    $ 62.38万
  • 项目类别:
The Organizational Hub and Web Portal for the 4D Nucleome Network
4D 核组网络的组织中心和门户网站
  • 批准号:
    8988647
  • 财政年份:
    2015
  • 资助金额:
    $ 62.38万
  • 项目类别:
Mechanism of Atheroprone Mechanotransduction Studied By Single Cell Imaging
单细胞成像研究动脉粥样硬化的机械传导机制
  • 批准号:
    8615815
  • 财政年份:
    2013
  • 资助金额:
    $ 62.38万
  • 项目类别:
Mechanism of Atheroprone Mechanotransduction Studied By Single Cell Imaging
单细胞成像研究动脉粥样硬化的机械传导机制
  • 批准号:
    8787794
  • 财政年份:
    2013
  • 资助金额:
    $ 62.38万
  • 项目类别:
Role of Spatiotemporal Epigenetic Dynamics in Regulating Endothelial Gene Expressions under Flows
时空表观遗传动力学在调节流动下内皮基因表达中的作用
  • 批准号:
    10063534
  • 财政年份:
    2013
  • 资助金额:
    $ 62.38万
  • 项目类别:
Integration of single-cell imaging and multi-omics sequencing to study EC mechano-pathophysiology
整合单细胞成像和多组学测序来研究 EC 机械病理生理学
  • 批准号:
    10443151
  • 财政年份:
    2013
  • 资助金额:
    $ 62.38万
  • 项目类别:
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
  • 批准号:
    8332732
  • 财政年份:
    2012
  • 资助金额:
    $ 62.38万
  • 项目类别:
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
  • 批准号:
    9111932
  • 财政年份:
    2012
  • 资助金额:
    $ 62.38万
  • 项目类别:
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
  • 批准号:
    10448495
  • 财政年份:
    2012
  • 资助金额:
    $ 62.38万
  • 项目类别:

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