Novel mechanism of neural and muscular degeneration

神经和肌肉退化的新机制

基本信息

  • 批准号:
    10624824
  • 负责人:
  • 金额:
    $ 42.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Ant1 is the muscle/heart/central nervous system (CNS) isoform of adenine nucleotide translocase that is primarily involved in ATP/ADP exchange across the inner mitochondrial membrane (IMM). An increasing number of missense mutations in Ant1 are found to cause dominant diseases that affect skeletal muscle and the central nervous system. These diseases are commonly manifested by fractional mtDNA deletions and mild bioenergetic defects. The mechanism of neuromuscular damage in the diseases is poorly understood. Interestingly, our recent studies in yeast and cultured human cells suggested that the mutant Ant1 is misfolded. This leads to cell death by a novel mechanism that we named mitochondrial Precursor Overaccumulation Stress (mPOS). mPOS is characterized by the toxic accumulation and aggregation of un-imported mitochondrial preproteins in the cytosol. These findings led to the central hypothesis that the mutant Ant1 primarily affects mitochondrial protein import. This results in mPOS in the cytosol, which plays an important role in inducing neural and muscular degeneration. Fractional mtDNA deletions occur independent of nucleotide transport activity, likely as a secondary damage collateral to reduced mitochondrial protein import. In this application, we propose to directly test this hypothesis in mouse models. We successfully generated knock-in (KI) mouse lines expressing misfolded variants of Ant1. Preliminary studies indicated that these mice develop phenotypes consistent with neural and muscular degeneration. In Specific Aim 1, we will use these unique experimental models to test the hypothesis that misfolded Ant1 induces neural and muscular degeneration and mtDNA instability independent of nucleotide transport. In Specific Aim 2, we will use various experimental tools that we developed in yeast, cultured human cells and the Ant1-KI mice to test the hypothesis that the misfolded Ant1 (or Aac2 in yeast) causes structural and functional damage to the mitochondrial protein import machinery and induces mPOS in the cytosol. In Specific Aim 3, we will determine the mechanisms that protect cells against Ant1-induced protein import stress and mPOS. Success of the project will establish a mouse model of protein import stress associated with mPOS. Particularly, validation of the mPOS model would help reconciling the mitochondrial and proteostatic pathways in many neural and muscular degenerative diseases. Finally, the results could have important implications for the understanding and therapy of Ant1-induced diseases, as well as many other clinical conditions that directly or indirectly affect mitochondrial protein import.
Ant1是肌肉/心脏/中枢神经系统(CNS)腺嘌呤核苷酸转位酶的异构体

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 }}

Xin Jie Chen其他文献

Xin Jie Chen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('Xin Jie Chen', 18)}}的其他基金

A novel mitochondria-to-lysosome stress signaling pathway in degenerative disease and aging
退行性疾病和衰老中一种新的线粒体到溶酶体应激信号通路
  • 批准号:
    10722759
  • 财政年份:
    2023
  • 资助金额:
    $ 42.51万
  • 项目类别:
Novel mechanism of neural and muscular degeneration
神经和肌肉退化的新机制
  • 批准号:
    10247517
  • 财政年份:
    2020
  • 资助金额:
    $ 42.51万
  • 项目类别:
Novel mechanism of neural and muscular degeneration
神经和肌肉退化的新机制
  • 批准号:
    10414131
  • 财政年份:
    2020
  • 资助金额:
    $ 42.51万
  • 项目类别:
Mechanism of Mitochondria-induced Progressive Muscle Wasting
线粒体诱导进行性肌肉萎缩的机制
  • 批准号:
    10062793
  • 财政年份:
    2019
  • 资助金额:
    $ 42.51万
  • 项目类别:
Mechanism of Mitochondria-induced Progressive Muscle Wasting
线粒体诱导进行性肌肉萎缩的机制
  • 批准号:
    10539303
  • 财政年份:
    2019
  • 资助金额:
    $ 42.51万
  • 项目类别:
Mechanism of Mitochondria-induced Progressive Muscle Wasting
线粒体诱导进行性肌肉萎缩的机制
  • 批准号:
    10348145
  • 财政年份:
    2019
  • 资助金额:
    $ 42.51万
  • 项目类别:
Aging-related mitochondrial degeneration and degenerative diseases
与衰老相关的线粒体变性和退行性疾病
  • 批准号:
    8277247
  • 财政年份:
    2005
  • 资助金额:
    $ 42.51万
  • 项目类别:
Ant-induced cell death and human degenerative diseases
蚂蚁诱导的细胞死亡和人类退行性疾病
  • 批准号:
    7438806
  • 财政年份:
    2005
  • 资助金额:
    $ 42.51万
  • 项目类别:
Ant-induced cell death and human degenerative diseases
蚂蚁诱导的细胞死亡和人类退行性疾病
  • 批准号:
    7364643
  • 财政年份:
    2005
  • 资助金额:
    $ 42.51万
  • 项目类别:
Aging-related mitochondrial degeneration and degenerative diseases
与衰老相关的线粒体变性和退行性疾病
  • 批准号:
    8459464
  • 财政年份:
    2005
  • 资助金额:
    $ 42.51万
  • 项目类别:

相似海外基金

The Role of Adenine Nucleotide Translocase in Mitochondrial Dysfunction Associated Senescence in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在慢性阻塞性肺病(COPD)线粒体功能相关衰老中的作用
  • 批准号:
    10633608
  • 财政年份:
    2023
  • 资助金额:
    $ 42.51万
  • 项目类别:
Characterization of Adenine Nucleotide Translocase (ANT) and Actin-Interacting Protein 1 (AIP1) as Protectors Against Cigarette Smoke
腺嘌呤核苷酸转位酶 (ANT) 和肌动蛋白相互作用蛋白 1 (AIP1) 作为香烟烟雾保护剂的表征
  • 批准号:
    9917578
  • 财政年份:
    2019
  • 资助金额:
    $ 42.51万
  • 项目类别:
The Role of Adenine Nucleotide Translocase in the Protection of Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在保护慢性阻塞性肺疾病 (COPD) 气道上皮细胞中的作用
  • 批准号:
    10459434
  • 财政年份:
    2018
  • 资助金额:
    $ 42.51万
  • 项目类别:
The Role of Adenine Nucleotide Translocase in the Protection of Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在保护慢性阻塞性肺疾病 (COPD) 气道上皮细胞中的作用
  • 批准号:
    10226893
  • 财政年份:
    2018
  • 资助金额:
    $ 42.51万
  • 项目类别:
The Role of Adenine Nucleotide Translocase in the Protection of Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在保护慢性阻塞性肺疾病 (COPD) 气道上皮细胞中的作用
  • 批准号:
    9764469
  • 财政年份:
    2018
  • 资助金额:
    $ 42.51万
  • 项目类别:
HNE damage of adenine nucleotide translocase in ethanol-mediated neuron apoptosis
乙醇介导的神经元凋亡中腺嘌呤核苷酸转位酶的 HNE 损伤
  • 批准号:
    7934507
  • 财政年份:
    2009
  • 资助金额:
    $ 42.51万
  • 项目类别:
Origin of mitochondrial proton leak: comparative investigation of Adenine Nucleotide, Translocase, Phosphate and Aspartat/Glutamate Carriers
线粒体质子泄漏的起源:腺嘌呤核苷酸、易位酶、磷酸盐和天冬氨酸/谷氨酸载体的比较研究
  • 批准号:
    40116377
  • 财政年份:
    2007
  • 资助金额:
    $ 42.51万
  • 项目类别:
    Research Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了