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中文摘要
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Friedreich氏共济失调(FA)是最常见的隐性遗传性共济失调,约占 共济失调诊所。FA是由单一的线粒体定位蛋白Frataxin缺乏引起的,约为10% 残留,以及这种线粒体蛋白耗竭的神经病理生理学和心脏病后果 最终都是致命的。我们最近首次证明了线粒体的生物发生 FA患者成纤维细胞和活体FA患者的血淋巴细胞中的缺陷与Frataxin缺陷成正比,以及 在FA模型小鼠的多个神经和肌肉组织中减少。线粒体生物发生的这种耗尽 而功能可能成为FA病理生理学和神经退行性变的主要驱动因素,即我们的前提是 说明Frataxin可降低→、有丝分裂原降低、→、FA、神经病理生理和神经退行性变。此外, 因为活体FA患者的外周血淋巴细胞出现有丝分裂缺陷的比例与他们的Frataxin成正比 缺乏,它可以提供一个重要的血液生物标记物的疾病病理生理和/或患者预后 临床药物试验。因此,我们建议研究有丝分裂缺陷在共济失调中的作用。 FA最佳小鼠模型FXNKD小鼠(Aim 1)的发病机制,Frataxin 减少导致有丝分裂缺陷(目标2),以及有丝分裂缺陷的相关性和稳定性 活体FA患者的外周血淋巴细胞及尸检FA靶点的有丝分裂原缺陷 经历神经变性和心脏变性的组织(目标3)。这些研究将澄清 线粒体生物发生中Frataxin依赖缺陷的病理机制贡献 FA最佳小鼠模型中的共济失调,及其作为生物标志物的价值,以及它与 在人类条件下的病理机制。
英文摘要
Friedreich's ataxia (FA) is the most common recessive inherited ataxia, comprising about half of patients seen in ataxia clinics. FA is caused by the deficiency of a single mitochondrially-localized protein, frataxin, to about 10% residual, and the neuropathophysiological and cardiological consequences of this mitochondrial protein depletion are ultimately lethal. We have recently demonstrated for the first time that there is a mitochondrial biogenesis defect proportional to the frataxin defect in FA patient fibroblasts and blood lymphocytes of living FA patients, and decreased in multiple neural and muscle tissues in FA mouse models. This depletion of mitochondrial biogenesis and function could turn out to be a major driver of FA pathophysiology and neurodegeneration, i.e. our premise is that frataxin decline→mitobiogenic decline→FA neuropathophysiology and neurodegeneration. Furthermore, because the mitobiogenesis defect occurs in blood lymphocytes of living FA patients in proportion to their frataxin deficiency, it could provide an important blood biomarker of disease pathophysiology and/or patient outcome for clinical drug trials. Thus we propose to investigate the contribution of the mitobiogenic defect to the ataxic pathomechanism in the best mouse model of FA, the FXNKD mouse (Aim 1), the mechanism by which frataxin decrease leads to the mitobiogenic defect (Aim 2), and the relevance and stability of the mitobiogenic defect in peripheral blood lymphocytes of living FA patients, and also mitobiogenic defects in autoptic FA human target tissues that experience neurodegeneration and cardiodegeneration (Aim 3). These studies will clarify the pathomechanistic contribution of the frataxin-dependent defect in mitochondrial biogenesis we identified to the ataxia in the best available mouse model of FA, and its value as a biomarker, and its relationship to the pathomechanism in the human condition.
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Mitochondrial-mediated Lung Injury mechanisms of QACs in vivo
  • 批准号:
    10675747
  • 项目类别:
  • 资助金额:
    $20.01万
  • 财政年份:
    2022
  • 负责人:
    Gino A Cortopassi
  • 依托单位:
Mitochondrial-mediated Lung Injury mechanisms of QACs in vivo
  • 批准号:
    10467271
  • 项目类别:
  • 资助金额:
    $23.93万
  • 财政年份:
    2022
  • 负责人:
    Gino A Cortopassi
  • 依托单位:
'Novel Shc Blockers as potential Alzheimer's Disease Therapeutics
  • 批准号:
    10395302
  • 项目类别:
  • 资助金额:
    $30.47万
  • 财政年份:
    2021
  • 负责人:
    Gino A Cortopassi
  • 依托单位:
'Novel Shc Blockers as potential Alzheimer's Disease Therapeutics
  • 批准号:
    10611613
  • 项目类别:
  • 资助金额:
    $32.94万
  • 财政年份:
    2021
  • 负责人:
    Gino A Cortopassi
  • 依托单位:
海外基金