Oxidation-dependent Regulation of MEF2D in Neuronal Stress

MEF2D 在神经元应激中的氧化依赖性调节

基本信息

  • 批准号:
    8911522
  • 负责人:
  • 金额:
    $ 2.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-09-01 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Neurons, when faced with endogenous and exogenous toxic stress, mobilize their survival machinery. Many human neurological diseases such as Alzheimer's and Parkinson's diseases involve altered neuronal survival and pathological loss of neurons. The long-term objective of this research in our laboratory is to understand at molecular level how neurons respond to stress and the role of dysfunction of survival response in neurodegenerative process. We propose in the current application to study how a neuronal survival protein myocyte enhancer factor 2D (MEF2D), which plays key roles in distinct cellular compartments, is regulated by toxic oxidative signals in neurons and models of neurodegenerative diseases. One of the key common pathways by which diverse toxic signals lead to neurodegenerative process involves oxidative stress and dysfunction of mitochondria. Indeed, several environmental toxicants and genetic alterations associated with AD and PD disrupt mitochondrial activity and induce oxidative stress. Recently, dysfunction of autophagic process has also been shown to play an important role in neuronal stress. However, the key links which propagate the initial oxidative insult in multi subcellular compartments to signal stress and impair survival remain largely unclear. Our previous work showed that nuclear transcription factor MEF2D strongly promotes the survival of several types of neurons. Our recent studies during the last funding cycle revealed that MEF2D is present in mitochondria to directly modulate mitochondrial function and non functional MEF2D is removed by chaperone mediated autophagy (CMA). Disruption of either process sensitizes neurons to stress, leading to death. These novel findings place MEF2D at a key position in multiple subcellular organelles, where it senses and modulates neuronal response to stress. Our preliminary studies suggest that oxidative stress directly modifies MEF2D molecule, impairing its function and regulation in these organelles. Together, these findings support the intriguing hypothesis that MEF2D is a key target of neuronal oxidation and impairment of its function at multi subcellular organelles underlies oxidation-induced stress and contribute to neurodegenerative process. We will combine molecular and cellular methods and animal models to determine in Aim I whether stress causes oxidative modifications of MEF2D in neurons; in Aim II whether oxidative modifications of MEF2D impair its function and regulation in multiple subcellular organelles in neurons; and in Aim III whether oxidative modifications of MEF2D occur in in vivo models of neurotoxin- induced degeneration and human postmortem brains. This study will identify MEF2D as a key target of oxidative stress in several key organelles and reveal that dysregulation of MEF2D by oxidative modifications may undermine neuronal survival. This novel mechanism may be relevant to the pathogenesis of neurodegenerative diseases and provide basis for developing novel therapeutic strategies for their treatment.
描述(由申请人提供):神经元,当面临内源性和外源性毒性应激时,动员其生存机制。许多人类神经系统疾病如阿尔茨海默病和帕金森病涉及改变的神经元存活和神经元的病理性损失。本研究的长期目标是在分子水平上了解神经元对应激的反应以及生存反应功能障碍在神经退行性变过程中的作用。我们在当前的申请中提出研究神经元存活蛋白肌细胞增强因子2D(MEF 2D)如何在神经元和神经退行性疾病模型中受到毒性氧化信号的调节,所述神经元存活蛋白肌细胞增强因子2D在不同的细胞隔室中起关键作用。 氧化应激和线粒体功能障碍是多种毒性信号导致神经退行性病变的关键共同途径之一。事实上,与AD和PD相关的几种环境毒物和遗传改变破坏线粒体活性并诱导氧化应激。近年来,自噬过程的功能障碍也被证明在神经元应激中起重要作用。然而,在多个亚细胞区室中传播初始氧化损伤以信号应激和损害存活的关键环节在很大程度上仍不清楚。我们以前的工作表明,核转录因子MEF 2D强烈促进几种类型的神经元的存活。我们最近在上一个资助周期的研究表明,MEF 2D存在于线粒体中,直接调节线粒体功能,而非功能性MEF 2D通过分子伴侣介导的自噬(CMA)去除。任何一个过程的破坏都会使神经元对压力敏感,从而导致死亡。这些新的发现将MEF 2D置于多个亚细胞器的关键位置,在那里它可以感知和调节神经元对压力的反应。我们的初步研究表明,氧化应激直接修饰MEF 2D分子,损害其在这些细胞器中的功能和调节。总之,这些发现支持了一个有趣的假设,即MEF 2D是神经元氧化的关键靶点,其在多个亚细胞器中的功能受损是氧化诱导的应激的基础,并有助于神经退行性过程。我们将结合联合收割机分子和细胞方法以及动物模型来确定目标I中应激是否引起神经元中MEF 2D的氧化修饰;目标II中MEF 2D的氧化修饰是否损害其在神经元中多个亚细胞器中的功能和调节;以及目标III中MEF 2D的氧化修饰是否发生在神经毒素诱导的变性的体内模型和人类死后脑中。这项研究将确定MEF 2D作为几个关键细胞器中氧化应激的关键靶点,并揭示氧化修饰引起的MEF 2D失调可能会破坏神经元的存活。这种新的机制可能与神经退行性疾病的发病机制有关,并为开发新的治疗策略提供基础。

项目成果

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{{ truncateString('ZIXU MAO', 18)}}的其他基金

Chloride Homeostasis in Lysosomal Function and Parkinson's Disease
溶酶体功能和帕金森病中的氯稳态
  • 批准号:
    10656542
  • 财政年份:
    2022
  • 资助金额:
    $ 2.34万
  • 项目类别:
Chloride Homeostasis in Lysosomal Function and Parkinson's Disease
溶酶体功能和帕金森病中的氯稳态
  • 批准号:
    10515961
  • 财政年份:
    2022
  • 资助金额:
    $ 2.34万
  • 项目类别:
Dysregulation of Multivesicular Body and Exosome Flux in Alzheimer's Disease
阿尔茨海默病中多泡体和外泌体通量的失调
  • 批准号:
    10213490
  • 财政年份:
    2021
  • 资助金额:
    $ 2.34万
  • 项目类别:
Chaperone-mediated Autophagy and Synaptic Dysfunction in Parkinson's Disease
帕金森病中分子伴侣介导的自噬和突触功能障碍
  • 批准号:
    10248292
  • 财政年份:
    2018
  • 资助金额:
    $ 2.34万
  • 项目类别:
Chaperone-mediated Autophagy and Synaptic Dysfunction in Parkinson's Disease
帕金森病中分子伴侣介导的自噬和突触功能障碍
  • 批准号:
    10427401
  • 财政年份:
    2018
  • 资助金额:
    $ 2.34万
  • 项目类别:
The Role of Drosha in the Pathogenesis of Alzheimer's Disease
Drosha 在阿尔茨海默病发病机制中的作用
  • 批准号:
    9976598
  • 财政年份:
    2016
  • 资助金额:
    $ 2.34万
  • 项目类别:
The Role of Drosha in the Pathogenesis of Alzheimer's Disease
Drosha 在阿尔茨海默病发病机制中的作用
  • 批准号:
    9323608
  • 财政年份:
    2016
  • 资助金额:
    $ 2.34万
  • 项目类别:
ER SIGNAL AND CHAPERONE-MEDIATED AUTOPHAGY IN NEURONAL STRESS
神经元应激中的 ER 信号和伴侣介导的自噬
  • 批准号:
    8504281
  • 财政年份:
    2013
  • 资助金额:
    $ 2.34万
  • 项目类别:
ER SIGNAL AND CHAPERONE-MEDIATED AUTOPHAGY IN NEURONAL STRESS
神经元应激中的 ER 信号和伴侣介导的自噬
  • 批准号:
    8811485
  • 财政年份:
    2013
  • 资助金额:
    $ 2.34万
  • 项目类别:
ER SIGNAL AND CHAPERONE-MEDIATED AUTOPHAGY IN NEURONAL STRESS
神经元应激中的 ER 信号和伴侣介导的自噬
  • 批准号:
    9240687
  • 财政年份:
    2013
  • 资助金额:
    $ 2.34万
  • 项目类别:

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