Role of Plasminogen Activator Inhibitor-1 in Vascular Smooth Muscle Cell Stiffening and Senescence

纤溶酶原激活剂抑制剂 1 在血管平滑肌细胞硬化和衰老中的作用

基本信息

  • 批准号:
    10512042
  • 负责人:
  • 金额:
    --
  • 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:
    2021-10-01 至 2025-09-30
  • 项目状态:
    未结题

项目摘要

Vascular smooth muscle cells (SMCs) are present throughout the arterial tree and play a central role in cardiovascular physiology by regulating blood pressure and flow. Cardiovascular aging is characterized by pathologic changes in SMCs that contribute in a major way to high-burden diseases affecting US veterans, including hypertension, atherosclerosis, myocardial infarction, stroke, and peripheral artery disease. Two important phenotypic changes that occur in SMCs with aging are 1) stiffening, which produces hypertension and increases cardiac afterload, and 2) senescence, which is functionally defined as arrest of cell division and assumption of the senescence-associated secretory phenotype (SASP), a driver of vascular inflammation and fibrosis. Plasminogen activator inhibitor-1 (PAI-1), a member of the serpin superfamily of protease inhibitors, is the primary inhibitor of tissue-type plasminogen activator (t-PA) and urokinase (u-PA) and an important regulator of proteolysis and cell adhesion. PAI-1 expression increases with age and is associated with vascular fibrosis and generalized cell senescence. However, the specific effects of PAI-1 on SMC stiffening and senescence, as well as the mechanisms underlying them, are poorly understood. In preliminary studies involving pharmacologic and genetic modulation of PAI-1 expression in SMCs, we have shown that drug targeting of PAI-1 decreases SMC stiffness, assessed by atomic force microscopy (AFM), while also decreasing SMC cytoskeleton formation and enhancing activation of cofilin, which degrades filamentous (F)- actin. We also have demonstrated that PAI-1 promotes SMC senescence by a pathway involving the LDL receptor-related protein-1 (LRP1), while also dampening mitochondrial respiratory fitness, which is strongly linked to cell senescence. We have performed an RNA-sequencing analysis that has identified candidate signaling pathways mediating PAI-1’s effects on SMC stiffness and senescence. We also have generated mice with conditional knockout of PAI-1 in SMCs, which will enable us to study the significance of our findings in vivo. Based on our extensive preliminary data, we hypothesize that PAI-1 1) regulates SMC stiffness by controlling actin, myosin, and focal adhesion assembly in the cytoskeleton, and 2) promotes SMC senescence through adverse effects on mitochondrial energy substrate utilization and reactive oxygen species accrual. To test these hypotheses, we propose the following specific aims: 1) identify the intracellular signaling pathways by which PAI-1 regulates SMC stress fiber formation and stiffness, 2) determine the role of PAI-1 in regulating mitochondrial substrate utilization and reactive oxygen species accumulation in SMCs, probing underlying mechanisms, and 3) study the effects of pharmacologic and SMC-specific inhibition of PAI-1 on arterial stiffness and senescence in vivo. Several innovative strategies will be employed, including 1) AFM, 2) confocal fluorescence microscopy, 3) quantitative studies of PAI-1’s effects of F-actin, myosin, and focal adhesion assembly, 4) measurement of mitochondrial energy substrate utilization and membrane potential, and 5) novel murine models that enable quantification of the effects of systemic inhibition and SMC-specific deletion of PAI-1 on vascular stiffening and senescence in vivo. The experiments will be carried out by a highly experienced, multi-disciplinary team of scientists from the Truman VA Hospital, the University of Missouri School of Medicine, and the Dalton Cardiovascular Research Center. The significance of the proposed work is that it will 1) identify mechanisms by which PAI-1 and its pharmacological inhibition regulate key degenerative changes that occur in SMCs with aging, namely stiffening and senescence, and 2) translate these findings to the in vivo setting. The proposed experiments will yield important new information about the roles of PAI-1 and SMCs in vascular aging that are directly relevant to major cardiovascular diseases affecting the US veteran population. The studies also have great potential for transition to the clinical setting through the use of pharmacologic PAI-1 inhibitors.
血管平滑肌细胞(SMCs)存在于整个动脉树中,并在 调节血压和血流的心血管生理学。心血管衰老的特点是 在影响美国退伍军人的高负担疾病中起主要作用的SMC的病理变化, 包括高血压、动脉粥样硬化、心肌梗死、中风和外周动脉疾病。二 随着年龄的增长,在SMC中发生的重要表型变化是1)僵硬,这会产生高血压 并增加心脏后负荷,以及2)衰老,其功能定义为细胞分裂停止和 假设衰老相关分泌表型(SASP),血管炎症和 纤维化症。纤溶酶原激活物抑制物-1(PAI-1)是丝氨酸蛋白水解酶抑制物超家族的成员。 组织型纤溶酶原激活物(t-PA)和尿激活酶(u-PA)的主要抑制物 蛋白质分解和细胞黏附的调节剂。PAI-1的表达随着年龄的增长而增加,并与 血管纤维化和全身性细胞衰老。然而,PAI-1在SMC硬化中的特异性作用 衰老,以及衰老背后的机制,人们知之甚少。在初步研究中 涉及到药物和遗传对SMC中PAI-1表达的调节,我们已经证明了药物 通过原子力显微镜(AFM)评估,靶向PAI-1降低了SMC的硬度,同时也 减少SMC细胞骨架的形成,增强COFILIN的活性,从而降解丝状(F)- 肌动蛋白。我们还证明了PAI-1通过与低密度脂蛋白有关的途径促进SMC衰老 受体相关蛋白-1(LRP1),同时也抑制线粒体的呼吸适应性,这是强烈的 与细胞衰老有关。我们已经进行了RNA测序分析,确定了候选 介导纤溶酶原激活物-1的信号通路S对SMC僵硬和衰老的影响我们还产生了 在SMC中有条件地敲除PAI-1的小鼠,这将使我们能够研究我们的发现的意义 在活体内。根据我们广泛的初步数据,我们假设PAI-1通过以下方式调节SMC硬度 控制细胞骨架中的肌动蛋白、肌球蛋白和焦点黏附组装,以及2)促进SMC衰老 通过对线粒体能量、底物的利用和活性氧的积累产生不利影响。至 为了验证这些假说,我们提出了以下具体目标:1)确定细胞内信号通路 通过PAI-1调节SMC应力纤维的形成和僵硬;2)确定PAI-1在调节中的作用 线粒体底物利用和SMC中的活性氧积累,探查基础 3)研究PAI-1的药理和SMC特异性抑制对动脉粥样硬化的影响 体内僵硬和衰老。将采用几种创新战略,包括1)AFM,2) 共聚焦荧光显微镜,3)F-肌动蛋白、肌球蛋白和焦点对纤溶酶原激活物-1‘S作用的定量研究 黏附组装,4)线粒体能量底物利用率和膜电位的测量, 5)新的小鼠模型,能够量化全身抑制和SMC特异性的影响 PAI-1缺失对体内血管僵硬和衰老的影响。这些实验将由一名 来自加州大学杜鲁门退伍军人医院的经验丰富的多学科科学家团队 密苏里州医学院和道尔顿心血管研究中心。这一事件的意义 计划中的工作是:1)确定PAI-1及其药理抑制调节机制 随着年龄的增长,SMC发生的关键退行性变化,即僵硬和衰老,以及2)翻译 这些发现与活体环境相吻合。拟议中的实验将产生关于 PAI-1和SMC在血管衰老中的作用与主要心血管疾病直接相关 美国退伍军人人数。这些研究也有很大的潜力通过以下方式过渡到临床环境 药物性PAI-1抑制剂的使用。

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 }}

William P Fay其他文献

William P Fay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('William P Fay', 18)}}的其他基金

Role of Plasminogen Activator Inhibitor-1 in Vascular Smooth Muscle Cell Stiffening and Senescence
纤溶酶原激活剂抑制剂 1 在血管平滑肌细胞硬化和衰老中的作用
  • 批准号:
    10259921
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
  • 批准号:
    10312631
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
  • 批准号:
    10230468
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
  • 批准号:
    10475264
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
  • 批准号:
    10240635
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
  • 批准号:
    10022343
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
  • 批准号:
    10730211
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
  • 批准号:
    9897387
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Role of Plasminogen Activator Inhibitor-1 in Adipose Tissue Dysfunction and Atherosclerosis in Metabolic Syndrome
纤溶酶原激活剂抑制剂 1 在代谢综合征脂肪组织功能障碍和动脉粥样硬化中的作用
  • 批准号:
    9913573
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Role of Plasminogen Activator Inhibitor-1 in Adipose Tissue Dysfunction and Atherosclerosis in Metabolic Syndrome
纤溶酶原激活剂抑制剂 1 在代谢综合征脂肪组织功能障碍和动脉粥样硬化中的作用
  • 批准号:
    10155514
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:

相似海外基金

Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
  • 批准号:
    10591918
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
  • 批准号:
    23K15383
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
  • 批准号:
    23H03556
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
  • 批准号:
    23K17212
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
  • 批准号:
    22H03519
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
  • 批准号:
    563657-2021
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
    Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10521849
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10671022
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
  • 批准号:
    10670918
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
  • 批准号:
    2706416
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了