PKC Epsilon in Vascular Dysfunction

PKC Epsilon 在血管功能障碍中的应用

基本信息

  • 批准号:
    8329950
  • 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:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-07-01 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the leading cause of death in the developed countries. Diabetes mellitus markedly increases the risk of atherosclerotic complications. Emerging evidence suggests that resistin, a novel adipokine implicated in insulin resistin, contributes to atherosclerotic disease and the poor interventional outcomes among diabetic population. We and others have shown that resistin significantly induces vascular smooth muscle cell (VSMC) dysfunction, a key step in intimal hyperplasia and restenosis. However, little is known about the underlying mechanisms and the treatment option is largely lacking. Recently, we demonstrated that the cellular effect of resistin was mediated by PKC-[. Our research team also showed that activating PKC-¿ protected against ischemia/reperfusion injury of transplanted myocardium and inhibiting PKC-¿ mitigated intimal hyperplasia in rat. Although therapeutically targeting PKC-¿ in the treatment of atherosclerotic complications is largely unknown. Based on our novel, seemingly controversial observations, we believe that the involvement of PKC-¿ in cardiovascular disease is a dynamic process. Acute activation of PKC-¿ protects against ischemia/reperfusion-induced cellular injuries whereas sustained inhibition of PKC-¿ following procedures can minimize resistin-induced intimal hyperplasia and restenosis. It is our fundamental hypothesis that time-specific PKC-¿ modulation reduces resistin-induced intimal hyperplasia and restenosis. To pursue this hypothesis, we propose a more comprehensive investigation to elucidate the molecular mechanisms, cellular effects, and in vivo influences of PKC-¿ modulation in resistin-exaggerated cellular stress following vascular injury. Three specific aims (SA) are proposed. SA 1: Determine the role of PKC-¿ in resistin-induced cellular effects. In this SA, we will first confirm our preliminary findings and determine time-specific PKC-¿ modulation in VSMC. We will then explore the modulating effect of PKC-¿ using a novel activated macrophage-VSMC co-culture system. Lastly, we will verify the effects of resistin and PKC-¿ modulation in ex vivo human carotid plaques. SA 2: Characterize the molecular mechanisms of PKC-¿-dependent resistin-induced cellular distress. Using a HCASMC model, we will study the involvement of PKC-¿ in resistin-induced ROS over-production in the SA2a. We will also expand our preliminary observation by examining time-specific PKC-¿ modulation in known resistin-induced signaling pathways in SA2b. Lastly, we will explore novel PKC-¿-dependent downstream signaling pathway(s) using an unbiased proteomics approach and determine whether a novel PKC-¿-mediated molecular interaction, mitochondria aldehyde dehydrogenase (ALDH2), is involved in resistin- induced cellular dysfunction (SA2c). SA 3: Evaluate the effects PKC-¿ on resistin-augmented post-injury intimal hyperplasia in a murine model. We will independently modulate PKC-¿ before atrial clamping and after vascular interventions to determine the in vivo effects of time-specific PKC-¿ modulation on resistin-exacerbated intimal hyperplasia using a transgenic murine model. The potential application of novel PKC-¿ specific peptide modulators at specific time points, justified by successful completion of our aims, represents a novel therapeutic option. Deciphering clinically-relevant mechanism(s) of intimal hyperplasia and ultimately translating these into a novel therapeutic strategy to suppress disease progression supports our long-term goal of minimizing complications of cardiovascular diseases and improving the clinical outcome of cardiovascular procedures.
描述(由申请人提供): 在发达国家,动脉粥样硬化是导致死亡的主要原因。糖尿病显著增加动脉粥样硬化并发症的风险。新出现的证据表明,一种新的脂肪因子,与胰岛素β-淀粉样蛋白有关,有助于动脉粥样硬化疾病和糖尿病人群中不良的干预结果。我们和其他人已经表明,β-氨基丁酸显著诱导血管平滑肌细胞(VSMC)功能障碍,这是内膜增生和再狭窄的关键步骤。然而,人们对潜在的机制知之甚少,治疗选择也很缺乏。最近,我们证明,PKC-介导的细胞作用的Bctin。本课题组还发现,激活PKC-<$保护大鼠移植心肌缺血/再灌注损伤,抑制PKC-<$减轻内膜增生。尽管在动脉粥样硬化并发症的治疗中靶向PKC-β的治疗在很大程度上是未知的。基于我们新颖的、看似有争议的观察,我们认为PKC-κ参与心血管疾病是一个动态过程。PKC的急性激活防止缺血/再灌注诱导的细胞损伤,而持续抑制PKC-β可以最大限度地减少抵抗素诱导的内膜增生和再狭窄。我们的基本假设是,时间特异性PKC-β调节减少抵抗素诱导的内膜增生和再狭窄。为了追求这一假设,我们提出了一个更全面的调查,以阐明分子机制,细胞效应,并在体内的影响,PKC-<$调制抵抗夸大细胞应激血管损伤后。提出了三个具体目标(SA)。SA 1:确定PKC-β在抵抗素诱导的细胞效应中的作用。在本SA中,我们将首先确认我们的初步研究结果,并确定VSMC中时间特异性PKC-β调节。然后,我们将探讨PKC-<$的调节作用,使用一种新的活化巨噬细胞-VSMC共培养系统。最后,我们将验证在离体人颈动脉斑块中的β-淀粉样蛋白和PKC-β调节的作用。SA 2:描述PKC-β依赖性抵抗素诱导细胞窘迫的分子机制。使用HCASMC模型,我们将研究PKC-â参与SA 2a中抵抗素诱导的活性氧过量产生。我们还将通过检查SA 2b中已知抵抗素诱导的信号通路中的时间特异性PKC-<$调制来扩展我们的初步观察。最后,我们将使用无偏蛋白质组学方法探索新的PKC-β依赖性下游信号传导途径,并确定新的PKC-β介导的分子相互作用,线粒体醛脱氢酶(ALDH 2)是否参与了β-内酰胺酶诱导的细胞功能障碍(SA 2c)。SA 3:在小鼠模型中评价PKC-β对抵抗素增强的损伤后内膜增生的影响。我们将在心房阻断前和血管介入后独立调节PKC-<$,以确定使用转基因小鼠模型的时间特异性PKC-<$调节对抵抗素加剧的内膜增生的体内作用。新型PKC-â特异性肽调节剂在特定时间点的潜在应用,通过成功完成我们的目标而得到证明,代表了一种新的治疗选择。解读内膜增生的临床相关机制,并最终将其转化为抑制疾病进展的新型治疗策略,支持我们最大限度地减少心血管疾病并发症和改善心血管手术临床结局的长期目标。

项目成果

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Wei Zhou其他文献

Spin Waves Excitations of Co/PtMultilayers
Co/Pt 多层膜的自旋波激发

Wei Zhou的其他文献

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{{ truncateString('Wei Zhou', 18)}}的其他基金

Targeting LKB1-null lung adenocarcinoma with innate immune system
利用先天免疫系统靶向 LKB1 缺失的肺腺癌
  • 批准号:
    10752833
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
An integrative approach to disease gene discovery combining genetic variation, gene expression, and epigenetics.
结合遗传变异、基因表达和表观遗传学的疾病基因发现的综合方法。
  • 批准号:
    10581608
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
An integrative approach to disease gene discovery combining genetic variation, gene expression, and epigenetics.
结合遗传变异、基因表达和表观遗传学的疾病基因发现的综合方法。
  • 批准号:
    10349878
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Role of orexin/hypocretin circuit in anesthesia and analgesia
食欲素/下丘脑分泌素回路在麻醉和镇痛中的作用
  • 批准号:
    10651642
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Role of orexin/hypocretin circuit in anesthesia and analgesia
食欲素/下丘脑分泌素回路在麻醉和镇痛中的作用
  • 批准号:
    10186780
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Role of orexin/hypocretin circuit in anesthesia and analgesia
食欲素/下丘脑分泌素回路在麻醉和镇痛中的作用
  • 批准号:
    10430182
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Role of orexin/hypocretin circuit in anesthesia and analgesia
食欲素/下丘脑分泌素回路在麻醉和镇痛中的作用
  • 批准号:
    10040369
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
PKC Epsilon in Vascular Dysfunction
PKC Epsilon 在血管功能障碍中的应用
  • 批准号:
    8536078
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
PKC Epsilon in Vascular Dysfunction
PKC Epsilon 在血管功能障碍中的应用
  • 批准号:
    8698299
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Pro-Oncogenic Role of LKB1 in NSCLC
LKB1 在 NSCLC 中的促癌作用
  • 批准号:
    8830435
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:

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