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中文摘要
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项目总结 亨廷顿病(HD)是一种进行性遗传性疾病,具有毁灭性的运动和认知缺陷,并 没有治疗方法可以阻止或逆转这种疾病。监测疾病进展依赖于大脑成像 观察几个月的退化情况。因此,我们的长期目标是寻找新的外周治疗方法。 HD进展的靶点和生物标记物,易于访问和简单解释。了解 外周组织的基本病理生理机制,如骨骼肌,将提供新的 HD治疗的机会和可获得的生物标记物。尽管经典地被归类为 神经退行性疾病,HD患者和小鼠模型都表现出衰弱的肌肉病理。 我们之前在肌氯通道(ClC-1)中发现了一种功能丧失,并向内整流 转基因R6/2亨廷顿病小鼠骨骼肌钾(KIR)通道,两者均有助于 肌肉过度兴奋。过度兴奋可以帮助解释僵硬、肌张力障碍、延迟的肌肉放松, 以及疾病中的运动迟缓。我们也显示了晚期神经肌肉传递的抑制。 R6/2小鼠,这可以帮助解释亨廷顿病患者的运动不耐受。我们没有发现 失神经的证据支持这样一种可能性,即这些缺陷是由于突变的亨廷顿蛋白在 肌肉。此外,抑制的传递似乎补偿了肌肉在晚期的过度兴奋。 R6/2期小鼠。因此,我们假设亨廷顿病骨骼肌的原发缺陷 导致神经肌肉传递的代偿性减少和运动的不稳定。至 检查神经肌肉传导抑制和/或肌肉缺陷在亨廷顿运动中的作用 根据症状,我们将测量对神经和直接肌肉刺激的反应产生的力量(目标1)。至 评估神经和肌肉之间的信号在疾病进展中的作用,我们将比较时间 神经肌肉缺陷发展到肌肉缺陷的时间过程(目标2)。通过 发展和研究亨廷顿氏病的纯肌肉模型,我们将确定一个 驾驶肌肉的原发肌病和神经肌肉缺陷(目标3)。成功实现这些目标 将提供迄今为止关于HD一般突触功能的最完整的描述和进一步的支持 他们假设HD也是一种原发肌病。通过研究肌肉和肌肉之间的关系 R6/2小鼠的神经肌肉缺陷我们将开始定义神经元和肌肉缺陷在 运动症状。最后,我们发现的缺陷可能会被新的治疗方法瞄准,并将很快 转化为与合作者开发疾病进展所需的外周生物标记物。
英文摘要
PROJECT SUMMARY Huntington’s disease (HD) is a progressive genetic disorder with devastating motor and cognitive defects and no therapies to stop or reverse the disease. Monitoring disease progression relies on brain imaging over several months to observe degeneration. Thus, our long-term objective is to identify new peripheral therapeutic targets and biomarkers of HD progression that are easy to access and simple to interpret. Understanding of basic pathophysiological mechanisms in peripheral tissues, such as skeletal muscle, would provide new opportunities for HD therapy and accessible biomarkers. Although classically categorized as a neurodegenerative disease, Both HD patients and mouse models present with debilitating muscle pathology. We previously discovered a loss-of-function in the muscle chloride channel (ClC-1) and inwardly rectifying potassium (Kir) channel in skeletal muscle from transgenic R6/2 Huntington’s disease mice, both contributing to muscle hyperexcitability. The hyperexcitability could help explain rigidity, dystonia, delayed muscle relaxations, and bradykinesia in the disease. We have also shown depressed neuromuscular transmission in late-stage R6/2 mice, which could help explain the motor impersistence in Huntington’s patients. That we found no evidence of denervation supports the possibility that these defects are due to mutant huntingtin expression in muscle. Moreover, the depressed transmission appears to compensate for the muscle hyperexcitability in late- stage R6/2 mice. Therefore, we hypothesis that primary defects in Huntington’s disease skeletal muscle result in compensatory decreases in neuromuscular transmission and motor impersistence. To examine the role of depressed neuromuscular transmission and/or muscle defects in Huntington’s motor symptoms, we will measure force generation in response to nerve and direct muscle stimulation (Aim 1). To assess the role of signaling between nerve and muscle during disease progression, we will compare the time course over which the neuromuscular defects develop to the time course of muscle defects (Aim 2). By developing and examining a muscle-only model of Huntington’s disease, we will determine the role of a primary myopathy in driving muscle and neuromuscular defects (Aim 3). Successfully completing these aims will provide the most complete characterization of general synaptic function in HD to date and further support they hypothesis that HD is also a primary myopathy. By examining the relationship between the muscle and neuromuscular defects in R6/2 mice we will begin to define the role of neuronal and muscle defects in the motor symptoms. Finally, the defects we identify could be targeted by novel therapeutics and will quickly translate to the development of needed peripheral biomarkers of disease progression with collaborators.
期刊论文(7)
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会议论文
DOI: 10.7554/elife.65691
发表时间: 2021-04-27
期刊: eLife
影响因子: 7.7
作者: [Myers JH, Denman K, DuPont C, Hawash AA, Novak KR, Koesters A, Grabner M, Dayal A, Voss AA, Rich MM]
通讯作者: Rich MM
Mechanisms of altered skeletal muscle action potentials in the R6/2 mouse model of Huntington's disease.
亨廷顿病 R6/2 小鼠模型中骨骼肌动作电位改变的机制。
DOI: 10.1152/ajpcell.00153.2020
发表时间: 2020
期刊: American journal of physiology. Cell physiology
影响因子: --
作者: [Miranda,DanielR, Reed,Eric, Jama,Abdulrahman, Bottomley,Michael, Ren,Hongmei, Rich,MarkM, Voss,AndrewA]
通讯作者: Voss,AndrewA
DOI: 10.7554/elife.71588
发表时间: 2022-01-05
期刊: eLife
影响因子: 7.7
作者: [Wang X, Nawaz M, DuPont C, Myers JH, Burke SR, Bannister RA, Foy BD, Voss AA, Rich MM]
通讯作者: Rich MM
DOI: 10.1016/j.bbrep.2021.101182
发表时间: 2021-12
期刊: Biochemistry and biophysics reports
影响因子: 2.7
作者: [Simpson B, Rich MM, Voss AA, Talmadge RJ]
通讯作者: Talmadge RJ
6
    Mechanism and function of a novel purinergic signaling cascade in skeletal muscle
    • 批准号:
      8267585
    • 项目类别:
    • 资助金额:
      $10.88万
    • 财政年份:
      2012
    • 负责人:
      Andrew Alvin Voss
    • 依托单位:
    Mechanism and function of a novel purinergic signaling cascade in skeletal muscle
    • 批准号:
      8626416
    • 项目类别:
    • 资助金额:
      $10.88万
    • 财政年份:
      2012
    • 负责人:
      Andrew Alvin Voss
    • 依托单位:
    Mechanism and function of a novel purinergic signaling cascade in skeletal muscle
    • 批准号:
      8448657
    • 项目类别:
    • 资助金额:
      $10.49万
    • 财政年份:
      2012
    • 负责人:
      Andrew Alvin Voss
    • 依托单位:
    Electrogenic glucose sensor of neuromuscular junction
    海外基金