Enhanced respiratory plasticity in models of respiratory motor neuron death

呼吸运动神经元死亡模型中呼吸可塑性增强

基本信息

  • 批准号:
    8635605
  • 负责人:
  • 金额:
    $ 10.44万
  • 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:
    2014-02-01 至 2015-01-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Candidate and Environment: The immediate and long-term goals of the candidate are to gain knowledge and experience necessary to become a successful academic researcher with an independent laboratory focused on the neural control of breathing. UW-Madison has many world-renowned respiratory physiologists that meet weekly for a respiratory neurobiology seminar series and journal club series making it a unique research environment in which the candidate can thrive. Thus, remaining at UW-Madison [will enable the candidate to be mentored by top-notch researchers in neuroplasticity and respiratory neurobiology (one of very few places studying this combination) and attain the required knowledge and experience to transition to independence.] Research: ALS is a devastating disease leading to progressive motor neuron degeneration and compromised breathing which ultimately leads to death. Despite its fundamental importance, respiratory insufficiency has seldom been studied in any ALS model. Thus, strategies to preserve adequate ventilatory function are needed to preserve life. The fundamental goal of this proposal is to identify compensatory mechanisms that trigger enhanced respiratory plasticity (intermittent hypoxia induced phrenic long-term facilitation; pLTF). Enhanced plasticity may allow us to restore phrenic motor output in models of respiratory motor neuron death, thereby preserving ventilatory capacity. We propose to study pLTF in rat models of respiratory motor neuron death including the progressive disease encountered in a genetic model of ALS (SOD1G93A rats) and a stable, inducible model (cholera toxin B conjugated to saporin; CTB-SAP). We propose to use a multidisciplinary approach including: 1) inducing respiratory motor neuron death using CTB-SAP; 2) phrenic nerve recordings to directly assess motor output; 3) RNAi in vivo to assess cellular mechanisms of AIH-induced pLTF in CTB-SAP rats; and 4) immunohistochemical methods to determine phrenic motor neuron survival and their expression of key molecules. [Three] specific aims are proposed: 1) increased SOD1G93A expression triggers compensatory increases in NADPH oxidase expression, thereby preserving ROS levels sufficient to express pLTF; [2) induced respiratory motor neuron death enhances pLTF; and 3) induced respiratory motor neuron death enhances pLTF by a mechanism distinct from that in SOD1G93A rats.] Since most ALS patients develop respiratory insufficiency, leading to ventilator dependence or death, our long-range goal is to develop new strategies to delay respiratory motor neuron death and enhance the functional capacity of spared motor neurons. Here we will harness mechanisms that increase function of surviving motor neurons (AIH-induced plasticity). These novel strategies, if successful, may guide future, translational studies in patients suffering from respiratory motor neuron death, including ALS patients. The present studies may have wide reaching benefits for non-respiratory motor pools in ALS, and other neurodegenerative diseases.
项目摘要/摘要 候选人和环境:候选人的近期和长期目标是获得知识和 成为一名成功的学术研究人员所需的经验,拥有专注于独立实验室的能力 关于呼吸的神经控制。威斯康星大学麦迪逊分校有许多世界知名的呼吸生理学家 每周一次的呼吸神经生物学研讨会系列和杂志俱乐部系列使其成为一项独特的研究 候选人能够茁壮成长的环境。因此,留在UW-Madison[将使候选人能够 由神经可塑性和呼吸神经生物学领域的顶尖研究人员指导(为数不多的地方之一 学习这一组合),并获得过渡到独立所需的知识和经验。] 研究:肌萎缩侧索硬化症是一种破坏性疾病,会导致运动神经元进行性退化和受损 最终导致死亡的呼吸。尽管呼吸功能不全很重要,但它已经 很少在任何ALS模型中进行研究。因此,需要采取策略来保持足够的呼吸功能。 来保护生命。这项提议的基本目标是确定引发 增强的呼吸可塑性(间歇性低氧诱导的膈神经长期易化;pLTF)。增强版 可塑性可能允许我们在呼吸运动神经元死亡的模型中恢复膈运动输出,从而 保持通气量。我们建议在大鼠呼吸运动神经元死亡模型中研究pLTF。 包括在ALS(SOD1G93A大鼠)遗传模型中遇到的进行性疾病和稳定的, 诱导模型(霍乱毒素B与皂苷偶联;CTB-SAP)。我们建议使用多学科的 方法包括:1)使用CTB-SAP诱导呼吸运动神经元死亡;2)膈神经记录 直接评估运动输出;3)体内RNAi评估AIH诱导的CTB-SAP pLTF的细胞机制 4)免疫组织化学方法检测大鼠膈运动神经元存活及其表达。 关键分子。[三]提出了具体目标:1)SOD1G93A表达增加触发补偿 增加NADPH氧化酶的表达,从而保持足以表达pLTF的ROS水平; 诱导呼吸运动神经元死亡增强pLTF;3)诱导呼吸运动神经元死亡 通过与SOD1G93A大鼠不同的机制增强pLTF。]由于大多数ALS患者都出现了 呼吸功能不全,导致呼吸机依赖或死亡,我们的长远目标是开发新的 延缓呼吸运动神经元死亡和提高备用运动功能的策略 神经元。在这里,我们将利用增加存活运动神经元(AIH诱导的)功能的机制 可塑性)。这些新的策略,如果成功,可能会指导未来对患者进行的翻译研究 由呼吸运动神经元死亡引起,包括ALS患者。目前的研究可能具有广泛的影响。 对肌萎缩侧索硬化症和其他神经退行性疾病的非呼吸性运动池的好处。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Hypoglossal Motor Neuron Death Via Intralingual CTB-saporin (CTB-SAP) Injections Mimic Aspects of Amyotrophic Lateral Sclerosis (ALS) Related to Dysphagia.
  • DOI:
    10.1016/j.neuroscience.2018.08.026
  • 发表时间:
    2018-10-15
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Lind LA;Murphy ER;Lever TE;Nichols NL
  • 通讯作者:
    Nichols NL
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Nicole L. Nichols其他文献

<em>Ighmbp2</em> mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S
  • DOI:
    10.1016/j.expneurol.2024.115025
  • 发表时间:
    2025-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Sara M. Ricardez Hernandez;Bassil Ahmed;Yaser Al Rawi;F. Javier Llorente Torres;Mona O. Garro Kacher;Catherine L. Smith;Zayd Al Rawi;Jessica Garcia;Nicole L. Nichols;Christian L. Lorson;Monique A. Lorson
  • 通讯作者:
    Monique A. Lorson

Nicole L. Nichols的其他文献

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{{ truncateString('Nicole L. Nichols', 18)}}的其他基金

Enhanced respiratory plasticity in models of respiratory motor neuron death
呼吸运动神经元死亡模型中呼吸可塑性增强
  • 批准号:
    9014557
  • 财政年份:
    2014
  • 资助金额:
    $ 10.44万
  • 项目类别:
Enhanced respiratory plasticity in models of respiratory motor neuron death
呼吸运动神经元死亡模型中呼吸可塑性增强
  • 批准号:
    9212843
  • 财政年份:
    2014
  • 资助金额:
    $ 10.44万
  • 项目类别:

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