Mitochondria fission and fusion (MFF)-dependent mechanisms in neuronal toxicity

神经元毒性中线粒体裂变和融合(MFF)依赖性机制

基本信息

  • 批准号:
    8811493
  • 负责人:
  • 金额:
    $ 33.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-03-01 至 2018-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Mitochondria play a central role in cell bioenergetics and control multiple aspects of neuronal life and death, including regulation of Ca2+ signaling. By buffering Ca2+ during excitation, and subsequently releasing Ca2+ back to the cytosol, mitochondria shape [Ca2+]i signals and regulate numerous Ca2+-dependent functions in neurons, such as excitability, synaptic plasticity and gene expression. However, excessive load of mitochondria with Ca2+ trigger neurotoxic processes in stroke and in Alzheimer's, Parkinson's and Huntington's diseases. In spite of the importance of neuronal mitochondrial Ca2+ transport, the molecules mediating mitochondrial Ca2+ uptake and release in neurons are not known. This knowledge gap presents a major obstacle in our progress toward understanding and therapeutically exploiting mitochondrial functions. Thus, the first objective of this proposal is to identify the molecular components of mitochondrial Ca2+ uptake in neurons. Mitochondria are highly dynamic organelles that rapidly undergo fission and fusion (MFF), which affects transport of mitochondria, synaptic plasticity and neuronal survival. Notably, mitochondrial fission is an early event in stroke, and fragmented mitochondria are prevalent in Alzheimer's and Huntington's disease. Given the central role of mitochondrial Ca2+ transport in neuronal life and death, it is possible that the effects of MFF on neuronal survival are mediated in part through changes in mitochondrial Ca2+ handling, although this idea has not been tested. Thus, our second objective is to determine how MFF status affects mitochondrial Ca2+ transport and Ca2+ homeostasis in neurons. Based on our preliminary data and published literature, we hypothesize that CCDC109A, CCDC109B and MICU1-3 are essential molecular components of mitochondrial Ca2+ uptake in neurons, and that the MFF process provides important control of CCDC109A and/or CCDC109B activities, mitochondrial Ca2+ transport and Ca2+ homeostasis in neurons exposed to neurotoxic conditions. We will use innovative approaches, including genetically encoded mitochondrial Ca2+ sensors, electron probe X-ray microanalysis and novel genetic mouse strains, to test our hypothesis in three specific aims. Aim 1 will identify the roles of novel proteins CCDC109A, CCDC109B and MICU1, 2 and 3 in mitochondrial Ca2+ uptake in neurons. Aim 2 will determine how mitochondrial restructuring regulates mitochondrial Ca2+ transport in neurons and examine specific roles of CCDC109A and CCDC109B phosphorylation in this process. Aim 3 will examine the function of MFF in maintaining neuronal Ca2+ homeostasis under neurotoxic conditions, such as excessive exposure to glutamate and ischemia. This project will provide insight into the molecular organization of mitochondrial Ca2+ transport in neurons and will establish mechanistic links between mitochondrial dynamics, Ca2+ signaling and neuronal Ca2+ homeostasis. We anticipate that these studies will be transformative because they will identify new molecular and genetic tools for exploring many functions of mitochondrial Ca2+ uptake in neurons and may lead to new therapeutics targeting mitochondrial Ca2+ transport and MFF for treating stroke and neurodegeneration.
描述(由申请人提供):线粒体在细胞生物能量学和控制神经元生命和死亡的多个方面发挥核心作用,包括Ca2+信号的调节。通过在兴奋期间缓冲Ca2+,随后将Ca2+释放回细胞质,线粒体形成[Ca2+]i信号并调节神经元中许多Ca2+依赖的功能,如兴奋性、突触可塑性和基因表达。然而,在中风、阿尔茨海默病、帕金森病和亨廷顿病中,线粒体Ca2+的过度负荷会触发神经毒性过程。尽管神经元线粒体Ca2+运输的重要性,介导线粒体Ca2+摄取和释放在神经元中的分子是未知的。这种知识差距是我们理解和治疗利用线粒体功能的主要障碍。因此,本提案的第一个目标是确定神经元中线粒体Ca2+摄取的分子成分。线粒体是一种高度动态的细胞器,可以快速进行裂变和融合(MFF),影响线粒体的运输、突触的可塑性和神经元的存活。值得注意的是,线粒体分裂是中风的早期事件,线粒体碎片化在阿尔茨海默氏症和亨廷顿氏症中很普遍。鉴于线粒体Ca2+转运在神经元生命和死亡中的核心作用,MFF对神经元存活的影响可能部分是通过线粒体Ca2+处理的变化介导的,尽管这一观点尚未得到验证。因此,我们的第二个目标是确定MFF状态如何影响神经元中线粒体Ca2+运输和Ca2+稳态。基于我们的初步数据和已发表的文献,我们假设CCDC109A、CCDC109B和MICU1-3是神经元线粒体Ca2+摄取的重要分子成分,并且MFF过程对暴露于神经毒性条件下的神经元的CCDC109A和/或CCDC109B活性、线粒体Ca2+运输和Ca2+稳态提供重要控制。我们将使用创新的方法,包括遗传编码的线粒体Ca2+传感器,电子探针x射线微分析和新的遗传小鼠菌株,在三个特定目标中测试我们的假设。目的1将确定新蛋白CCDC109A, CCDC109B和MICU1, 2和3在神经元线粒体Ca2+摄取中的作用。Aim 2将确定线粒体重组如何调节神经元中线粒体Ca2+转运,并检查CCDC109A和CCDC109B磷酸化在这一过程中的具体作用。目的3将研究MFF在神经毒性条件下维持神经元Ca2+稳态的功能,如过度暴露于谷氨酸和缺血。该项目将深入了解神经元中线粒体Ca2+运输的分子组织,并将建立线粒体动力学,Ca2+信号和神经元Ca2+稳态之间的机制联系。我们预计这些研究将是变革性的,因为它们将确定新的分子和遗传工具,用于探索神经元中线粒体Ca2+摄取的许多功能,并可能导致针对线粒体Ca2+运输和MFF治疗中风和神经变性的新疗法。

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 }}

Yuriy M Usachev其他文献

Yuriy M Usachev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('Yuriy M Usachev', 18)}}的其他基金

The mitochondrial Ca2+ uniporter in the regulation of neural activity and susceptibility to seizures
线粒体 Ca2 单向转运蛋白在神经活动和癫痫易感性调节中的作用
  • 批准号:
    10534197
  • 财政年份:
    2021
  • 资助金额:
    $ 33.03万
  • 项目类别:
The mitochondrial Ca2+ uniporter in the regulation of neural activity and susceptibility to seizures
线粒体 Ca2 单向转运蛋白在神经活动和癫痫易感性调节中的作用
  • 批准号:
    10392188
  • 财政年份:
    2021
  • 资助金额:
    $ 33.03万
  • 项目类别:
The Role of the Complement System in Spinal Mechanisms of Chronic Pain
补体系统在慢性疼痛脊柱机制中的作用
  • 批准号:
    10165843
  • 财政年份:
    2019
  • 资助金额:
    $ 33.03万
  • 项目类别:
The Role of the Complement System in Spinal Mechanisms of Chronic Pain
补体系统在慢性疼痛脊柱机制中的作用
  • 批准号:
    10408148
  • 财政年份:
    2019
  • 资助金额:
    $ 33.03万
  • 项目类别:
The Role of the Complement System in Spinal Mechanisms of Chronic Pain
补体系统在慢性疼痛脊柱机制中的作用
  • 批准号:
    10643985
  • 财政年份:
    2019
  • 资助金额:
    $ 33.03万
  • 项目类别:
The Role of the Complement System in Spinal Mechanisms of Chronic Pain
补体系统在慢性疼痛脊柱机制中的作用
  • 批准号:
    10572087
  • 财政年份:
    2019
  • 资助金额:
    $ 33.03万
  • 项目类别:
Molecular Mechanisms and Functions of Mitochondrial Ca2+ transport in Neurons
神经元线粒体 Ca2+ 转运的分子机制和功能
  • 批准号:
    9240345
  • 财政年份:
    2016
  • 资助金额:
    $ 33.03万
  • 项目类别:
Molecular Mechanisms and Functions of Mitochondrial Ca2+ transport in Neurons
神经元线粒体 Ca2+ 转运的分子机制和功能
  • 批准号:
    9752673
  • 财政年份:
    2016
  • 资助金额:
    $ 33.03万
  • 项目类别:
The Role of Ca-dependent Transcription Factor NFAT in Pain Control
Ca 依赖性转录因子 NFAT 在疼痛控制中的作用
  • 批准号:
    8943179
  • 财政年份:
    2015
  • 资助金额:
    $ 33.03万
  • 项目类别:
The Role of Ca-dependent Transcription Factor NFAT in Pain Control
Ca 依赖性转录因子 NFAT 在疼痛控制中的作用
  • 批准号:
    9064863
  • 财政年份:
    2015
  • 资助金额:
    $ 33.03万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 33.03万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了