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中文摘要
翻译
项目摘要/摘要 心肌细胞因凋亡和/或坏死而死亡是心脏缺血性损伤、病理性重构、 和终末期心力衰竭。与细胞凋亡相反,坏死在心脏病发病机制中的作用 在很大程度上没有得到充分的研究。新出现的证据已经确定了几种形式的“程序性坏死”,如 如死亡受体介导的坏死(称为“坏死性下垂”)、线粒体介导的坏死和氧化性 应激引起的坏死。程序性坏死在心脏中是如何调节的仍在很大程度上尚不清楚,而且 预防坏死仍然是一个重要的挑战。此外,目前还没有分子策略可用于 同时针对心脏病的多个细胞死亡过程。在这里,我们的初步研究发现了一种 CyLD(圆柱瘤病),一种赖氨酸63(K63)特异的脱泛素酶,作为一种关键的调节因子,其作用出人意料 心肌细胞的多种细胞死亡途径,包括细胞凋亡、坏死性下垂和氧化应激诱导 坏死。有趣的是,心肌缺血损伤后,CyLD的表达显著上调。vbl.使用 CyLD基因敲除和转基因小鼠模型,我们的初步数据进一步表明,CyLD基因敲除 心肌缺血损伤减轻,而CyLD过度表达则加重。重要的是,消融 CyLD抑制心肌细胞的凋亡、坏死性下垂和坏死,而CyLD过表达 结果显示出相反的效果。从机制上讲,我们的数据揭示了K63连接的多泛素化(K63-Ub)依赖 CyLD调控三种细胞死亡的泛素化状态和活性的细胞死亡信号机制 调节者:TRAF2、TAK1和AKT/PKB。因此,我们假设脱泛素酶CyLD是一个关键的调节因子。 是多种细胞死亡途径的重要组成部分,也是治疗心肌缺血损伤和重构的有效靶点。 使用遗传功能丧失和功能获得策略,我们将解决两个具体目标:目标1)研究 CyLD作为心肌细胞死亡、缺血损伤和重构的关键调节因子的新作用 基因敲除和转基因模型及AAV9-shCyLD载体。目的2)定义CyLD介导的K63-Ub 依赖细胞死亡信号网络调节心肌细胞的凋亡、坏死性下垂和坏死。这 该项目研究了心脏中一种新的CyLD介导的细胞死亡信号网络及其功能相关性 在心脏缺血损伤和重塑中的作用。此外,拟议的研究将定义K63-Ub依赖 调节细胞凋亡、坏死性下垂和坏死的机制,这构成了细胞死亡的新范式 监管。这些研究还提供了新的抗细胞死亡方法,具有重要的翻译意义。 策略,因为我们的初步结果揭示了CyLD作为多个细胞死亡过程的分子靶点。
英文摘要
Project Summary/Abstract Cardiac cell death by apoptosis and/or necrosis is a hallmark of cardiac ischemic injury, pathological remodeling, and end-stage heart failure. In contrast to apoptosis, the role of necrosis in the pathogenesis of heart disease has been largely understudied. Emerging evidence has identified several forms of “programmed necrosis”, such as death receptor-mediated necrosis (termed “necroptosis”), mitochondria-mediated necrosis, and oxidative stress-induced necrosis. How programmed necrosis is regulated in the heart remains largely unknown, and preventing necrosis is still an important challenge. Moreover, currently no molecular strategies are available to simultaneously target multiple cell death processes in heart disease. Here, our preliminary studies identified an unexpected role for CYLD (cylindromatosis), a lysine 63 (K63)-specific deubiquitinase, as a key regulator of multiple cell death pathways in cardiomyocytes, including apoptosis, necroptosis, and oxidative stress-induced necrosis. Intriguingly, CYLD expression was markedly upregulated in the heart following ischemic injury. Using Cyld knockout and transgenic mouse models, our preliminary data further show that ablation of CYLD attenuated, whereas overexpression of CYLD exacerbated, cardiac ischemic injury. Importantly, ablation of CYLD inhibited apoptosis, necroptosis, and necrosis in cardiomyocytes, whereas overexpression of CYLD showed the opposite effect. Mechanistically, our data reveal a K63-linked polyubiquitination (K63-Ub) dependent cell death signaling mechanism whereby CYLD controls the ubiquitination status and activity of three cell death regulators: TRAF2, TAK1 and AKT/PKB. Therefore, we hypothesize the deubiquitinase CYLD is a key regulator of multiple cell death pathways and a promising therapeutic target for cardiac ischemic injury and remodeling. Using genetic loss- and gain-of-function strategies, we will address two specific aims: Aim 1) To investigate the novel role of CYLD as a key regulator of myocardial cell death, ischemic injury, and remodeling using Cyld knockout and transgenic models and AAV9-shCYLD vectors. Aim 2) To define a CYLD-mediated, K63-Ub dependent cell death signaling network regulating apoptosis, necroptosis, and necrosis in cardiomyocytes. This project investigates a novel CYLD-mediated cell death signaling network in the heart and its functional relevance in cardiac ischemic injury and remodeling. Moreover, the proposed studies will define a K63-Ub dependent mechanism regulating apoptosis, necroptosis, and necrosis, which constitutes a new paradigm of cell death regulation. These studies also have important translational implications by providing new anti-cell death strategies, given our preliminary results revealing CYLD as a molecular target for multiple cell death processes.
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The Deubiquitinase CYLD Controls Multiple Cell Death Pathways in the Heart
  • 批准号:
    10545046
  • 项目类别:
  • 资助金额:
    $38.88万
  • 财政年份:
    2022
  • 负责人:
    Qinghang Liu
  • 依托单位:
A K63-Ubiquitination Dependent Necroptosis Signaling Network in the Heart
  • 批准号:
    10090946
  • 项目类别:
  • 资助金额:
    $38.88万
  • 财政年份:
    2021
  • 负责人:
    Qinghang Liu
  • 依托单位:
A K63-Ubiquitination Dependent Necroptosis Signaling Network in the Heart
  • 批准号:
    10543111
  • 项目类别:
  • 资助金额:
    $38.88万
  • 财政年份:
    2021
  • 负责人:
    Qinghang Liu
  • 依托单位:
A K63-Ubiquitination Dependent Necroptosis Signaling Network in the Heart
  • 批准号:
    10327275
  • 项目类别:
  • 资助金额:
    $38.88万
  • 财政年份:
    2021
  • 负责人:
    Qinghang Liu
  • 依托单位:
海外基金