Rapid ischemic tolerance: Ubiquitin-mediated structural reorganization

快速缺血耐受:泛素介导的结构重组

基本信息

项目摘要

DESCRIPTION (provided by applicant): Tolerance, the cellular response to mild stress, which protects against a toxic stress, is a conserved feature of many organisms. Most research has focused on long-term tolerance, which occurs 24-72 hours following preconditioning and is mediated by changes in gene expression. In contrast we have focused on short-term ischemic tolerance, which is mediated by rapid biochemical events and occurs 1 hour following the preconditioning. The identification of the mechanisms of short-term tolerance may identify novel rapid acting therapeutic targets to treat acute ischemic episodes (stroke). Our studies have suggested the ubiquitin-proteasome system, which regulates protein degradation, as being responsible for rapid ischemic tolerance. Using a proteomics screen we identified 2 candidate proteins, fascin and myristilated alanine-rich C kinase substrate (MARCKS), which are selectively ubiquitinated and degraded following preconditioning ischemia. The degradation of these candidate proteins results in the reorganization of the actin cytoskeleton, and may reduce NMDA receptor function, which is implicated in excitotoxic cell injury following ischemia. Our central hypothesis is the degradation of fascin and MARCKS following preconditioning ischemia, results in brief cytoskeleton re-arrangement and disruption of NMDA receptor function thereby protecting the brain from harmful ischemia. Our hypothesis will be tested using an in vitro model of ischemia. In Aim 1, Investigate the effect of preconditioning ischemia on cytoskeletal protein degradation by the ubiquitin-proteasome system, we will investigate the role of the ubiquitin-proteasome system on the rapid degradation of our two candidate proteins, fascin and MARCKS, following preconditioning ischemia. In the Aim 2, Investigate changes in postsynaptic structural reorganization in ischemic tolerance, we will study the effect of preconditioning ischemia on the reorganization of the postsynaptic membrane. Experiments will address the effect of preconditioning ischemia on the structure of dendrites. We will determine the relevance of actin reorganization on ischemic tolerance by using actin stabilizing/ destabilizing compounds. Using co- immunoprecipitation we will investigate actin-NMDA receptor interactions following preconditioning. Understanding how preconditioning remodels synaptic structure and function may help identify harmful vs. protective mechanisms induced by brief ischemia in the brain, and give a clearer understanding of brain cell death. We believe that the rapid and selective degradation of specific brain proteins induces a protective state and may reveal suitable targets for pharmacological therapeutics. Indeed, the long-term aim of these studies is to discover endogenous protective mechanisms that can be translated into effective rapid acting neuroprotective agents for stroke.
描述(由申请人提供):耐受性是细胞对轻度应激的反应,它可以防止毒性应激,是许多生物体的保守特征。大多数研究都集中在长期耐受性上,这种耐受性发生在预处理后24-72小时,由基因表达的变化介导。相比之下,我们关注的是短期缺血耐受性,它是由快速生化事件介导的,发生在预处理后1小时。短期耐受性机制的确定可能会发现治疗急性缺血性发作(中风)的新的速效治疗靶点。我们的研究表明,调控蛋白质降解的泛素-蛋白酶体系统是快速缺血耐受的原因。通过蛋白质组学筛选,我们确定了2种候选蛋白,束状蛋白和myristilated富含丙氨酸的C激酶底物(MARCKS),它们在预处理缺血后被选择性泛素化和降解。这些候选蛋白的降解导致肌动蛋白细胞骨架的重组,并可能降低NMDA受体的功能,这与缺血后的兴奋性毒性细胞损伤有关。我们的中心假设是,预适应缺血后,筋膜蛋白和MARCKS的降解导致细胞骨架的短暂重排和NMDA受体功能的破坏,从而保护大脑免受有害缺血的伤害。我们的假设将通过体外缺血模型进行验证。在Aim 1中,研究预处理缺血对泛素-蛋白酶体系统降解细胞骨架蛋白的影响,我们将研究泛素-蛋白酶体系统在预处理缺血后快速降解我们的两种候选蛋白,束状蛋白和marks的作用。在“研究缺血耐受中突触后结构重组的变化”中,我们将研究预适应缺血对突触后膜重组的影响。实验将探讨预处理缺血对树突结构的影响。我们将通过使用肌动蛋白稳定/不稳定化合物来确定肌动蛋白重组与缺血耐受性的相关性。使用共免疫沉淀,我们将研究肌动蛋白- nmda受体在预处理后的相互作用。了解预处理如何重塑突触结构和功能可能有助于识别大脑短暂缺血诱导的有害与保护机制,并更清楚地了解脑细胞死亡。我们认为,特定脑蛋白的快速和选择性降解诱导了一种保护状态,并可能揭示了药物治疗的合适靶点。事实上,这些研究的长期目标是发现内源性保护机制,这些机制可以转化为有效的快速作用的中风神经保护剂。

项目成果

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ROBERT MELLER其他文献

ROBERT MELLER的其他文献

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{{ truncateString('ROBERT MELLER', 18)}}的其他基金

Blood transcriptomics as CT adjuvant to exclude hemorrhage in acute stroke
血液转录组学作为 CT 佐剂排除急性中风出血
  • 批准号:
    10611988
  • 财政年份:
    2020
  • 资助金额:
    $ 16.93万
  • 项目类别:
Blood transcriptomics as CT adjuvant to exclude hemorrhage in acute stroke
血液转录组学作为 CT 佐剂排除急性中风出血
  • 批准号:
    10396630
  • 财政年份:
    2020
  • 资助金额:
    $ 16.93万
  • 项目类别:
Blood transcriptomics as CT adjuvant to exclude hemorrhage in acute stroke
血液转录组学作为 CT 佐剂排除急性中风出血
  • 批准号:
    10210310
  • 财政年份:
    2020
  • 资助金额:
    $ 16.93万
  • 项目类别:
Rapid ischemic tolerance: Synaptic re-organization and reduced excitotoxicity
快速缺血耐受:突触重组和兴奋性毒性降低
  • 批准号:
    8142097
  • 财政年份:
    2008
  • 资助金额:
    $ 16.93万
  • 项目类别:
Rapid ischemic tolerance: Synaptic re-organization and reduced excitotoxicity
快速缺血耐受:突触重组和兴奋性毒性降低
  • 批准号:
    8332845
  • 财政年份:
    2008
  • 资助金额:
    $ 16.93万
  • 项目类别:
Rapid ischemic tolerance: Synaptic re-organization and reduced excitotoxicity
快速缺血耐受:突触重组和兴奋性毒性降低
  • 批准号:
    7915525
  • 财政年份:
    2008
  • 资助金额:
    $ 16.93万
  • 项目类别:
Rapid ischemic tolerance: Synaptic re-organization and reduced excitotoxicity
快速缺血耐受:突触重组和兴奋性毒性降低
  • 批准号:
    7694369
  • 财政年份:
    2008
  • 资助金额:
    $ 16.93万
  • 项目类别:
Rapid ischemic tolerance: Synaptic re-organization and reduced excitotoxicity
快速缺血耐受:突触重组和兴奋性毒性降低
  • 批准号:
    7583695
  • 财政年份:
    2008
  • 资助金额:
    $ 16.93万
  • 项目类别:
Rapid ischemic tolerance: Ubiquitin-mediated structural reorganization
快速缺血耐受:泛素介导的结构重组
  • 批准号:
    7149477
  • 财政年份:
    2006
  • 资助金额:
    $ 16.93万
  • 项目类别:
Protein ubiquitination based neuroprotection for stroke
基于蛋白质泛素化的中风神经保护
  • 批准号:
    6862336
  • 财政年份:
    2005
  • 资助金额:
    $ 16.93万
  • 项目类别:

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由两类细菌肌动蛋白 MreB 驱动的新型运动系统
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研究肌动蛋白和微管如何协调及其相关性。
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