Mitochondria Dynamics Protein Drp1 in ROS Signaling, Endothelial Metabolism and Angiogenesis

线粒体动力学蛋白 Drp1 在 ROS 信号传导、内皮代谢和血管生成中的作用

基本信息

  • 批准号:
    10317794
  • 负责人:
  • 金额:
    $ 49.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

The aim of this grant is to elucidate the role of mitochondrial dynamics protein Drp1 as a novel redox sensor that transmits VEGF-derived H2O2 signaling to enhance angiogenesis via regulation of endothelial cell (EC) glycolysis. The induction of new blood vessels is critical for tissue repair in response to injury such as peripheral arterial disease (PAD), which is impaired in diabetes. Reactive oxygen species (ROS) such as H2O2 derived from NADPH oxidase (NOX) and mitochondria at normal level act as signaling molecules to promote VEGF-induced angiogenesis in endothelial cells (ECs) and reparative neovascularization. However, it remains unclear “how diffusible H2O2 signal can be specifically transmitted to promote therapeutic angiogenesis”. Signaling function of ROS is mainly through oxidation of reactive Cys residues to generate “Cysteine sulfenic acid (Cys-OH)” (sulfenylation) which is involved in disulfide bond formation with target protein and redox signaling. In addition, ECs utilize glycolysis as a major source of ATP to promote angiogenesis. However, the mechanistic link between NOX-mitochondrial ROS (mitoROS)/redox signaling and EC metabolism (glycolysis) in VEGF-induced angiogenesis is entirely unknown. Drp1 GTPase is key regulator of mitochondrial (mito) fission via its post translational modification, but its role in ROS dependent VEGFR2 signaling and angiogenesis in ECs and in vivo has never been reported. Our preliminary data are consistent with the hypothesis that VEGF induces sulfenylation of Drp1 via NOX-derived H2O2, which drives mito fission-mitoROS axis that promotes oxidative activation of key metabolic enzyme AMPK via disulfide bond formation (early phase) as well as PFKFB3 expression (late phase) in ECs. This in turn enhances endothelial glycolysis and angiogenesis required for restoring neovascularization in ischemic vascular disease. Aim1 will characterize the VEGF-induced Drp1 sulfenylation and establish its role in ROS-dependent angiogenic responses in ECs. Aim2 will determine the molecular mechanism by which VEGF-induced Drp1 sulfenylation promotes glycolysis via mitochondrial ROS-dependent manner in ECs. Aim 3 will determine the functional role of endothelial Drp1 in ROS-dependent reparative neovascularization and address underlying mechanisms in vivo using animal model of PAD (hindlimb ischemia model). We will also address how diabetes -induced excess ROS impair angiogenesis in ECs and in vivo by focusing on Drp1 phosphorylation at S616, but not Drp1-CysOH. We will use various innovative reagents, methods and mice including biotin-labelled Cys-OH trapping probe; BiFC-based protein-protein interaction in situ; real-time imaging of cytosol- and mitoROS using redox-sensitive biosensors; newly developed EC-specific Drp1-/- mice and CRISPR/Cas9-generated “redox dead” Cys oxidation-defective Drp1 or AMPK knock-in mutant mice. Our proposal will provide novel mechanistic insights into Cys oxidized mitochondrial fission protein Drp1 that orchestrates NOX/mito ROS signaling and glycolysis as a potential therapeutic target for treatment of ischemic cardiovascular diseases.
这项资助的目的是阐明线粒体动力学蛋白Drp1作为一种新型氧化还原传感器的作用

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Masuko Ushio-Fukai其他文献

Masuko Ushio-Fukai的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Masuko Ushio-Fukai', 18)}}的其他基金

Mitochondria Dynamics Protein Drp1 in ROS Signaling, Endothelial Metabolism and Angiogenesis
线粒体动力学蛋白 Drp1 在 ROS 信号传导、内皮代谢和血管生成中的作用
  • 批准号:
    10475228
  • 财政年份:
    2021
  • 资助金额:
    $ 49.52万
  • 项目类别:
Mitochondria Dynamics Protein Drp1 in ROS Signaling, Endothelial Metabolism and Angiogenesis
线粒体动力学蛋白 Drp1 在 ROS 信号传导、内皮代谢和血管生成中的作用
  • 批准号:
    10666540
  • 财政年份:
    2021
  • 资助金额:
    $ 49.52万
  • 项目类别:
Protein Disulfide Isomerase as Novel Redox Sensor in VEGF Signaling
蛋白质二硫键异构酶作为 VEGF 信号转导中的新型氧化还原传感器
  • 批准号:
    9479934
  • 财政年份:
    2016
  • 资助金额:
    $ 49.52万
  • 项目类别:
Role of Cysteine Sulfenic Acid Formation in Compartmentalization of VEGF Signalin
半胱氨酸磺酸形成在 VEGF 信号蛋白区室化中的作用
  • 批准号:
    8445715
  • 财政年份:
    2013
  • 资助金额:
    $ 49.52万
  • 项目类别:
Role of Cysteine Sulfenic Acid Formation in Compartmentalization of VEGF Signalin
半胱氨酸磺酸形成在 VEGF 信号蛋白区室化中的作用
  • 批准号:
    8620710
  • 财政年份:
    2013
  • 资助金额:
    $ 49.52万
  • 项目类别:
Reactive Oxygen Species and Endothelial Migration
活性氧和内皮迁移
  • 批准号:
    7844215
  • 财政年份:
    2009
  • 资助金额:
    $ 49.52万
  • 项目类别:
Reactive Oxygen Species and Endothelial Migration
活性氧和内皮迁移
  • 批准号:
    7097600
  • 财政年份:
    2006
  • 资助金额:
    $ 49.52万
  • 项目类别:
Reactive Oxygen Species and Endothelial Migration
活性氧和内皮迁移
  • 批准号:
    7379914
  • 财政年份:
    2006
  • 资助金额:
    $ 49.52万
  • 项目类别:
Reactive Oxygen Species and Endothelial Migration
活性氧和内皮迁移
  • 批准号:
    7322030
  • 财政年份:
    2006
  • 资助金额:
    $ 49.52万
  • 项目类别:
Reactive Oxygen Species and Endothelial Migration
活性氧和内皮迁移
  • 批准号:
    7579146
  • 财政年份:
    2006
  • 资助金额:
    $ 49.52万
  • 项目类别:

相似海外基金

Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
  • 批准号:
    2867610
  • 财政年份:
    2023
  • 资助金额:
    $ 49.52万
  • 项目类别:
    Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
  • 批准号:
    BB/W009633/1
  • 财政年份:
    2022
  • 资助金额:
    $ 49.52万
  • 项目类别:
    Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2021
  • 资助金额:
    $ 49.52万
  • 项目类别:
    Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
  • 批准号:
    459043
  • 财政年份:
    2021
  • 资助金额:
    $ 49.52万
  • 项目类别:
    Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2020
  • 资助金额:
    $ 49.52万
  • 项目类别:
    Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
  • 批准号:
    10561642
  • 财政年份:
    2019
  • 资助金额:
    $ 49.52万
  • 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2019
  • 资助金额:
    $ 49.52万
  • 项目类别:
    Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
  • 批准号:
    2243045
  • 财政年份:
    2019
  • 资助金额:
    $ 49.52万
  • 项目类别:
    Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
  • 批准号:
    10359032
  • 财政年份:
    2019
  • 资助金额:
    $ 49.52万
  • 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
  • 批准号:
    428988
  • 财政年份:
    2019
  • 资助金额:
    $ 49.52万
  • 项目类别:
    Studentship Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了