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：
9212843
负责人：
Nicole L. Nichols
金额：
$ 23.83万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
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 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212843
关键词：
Activities of Daily Living Acute Adenosine Affect Aftercare Amyotrophic Lateral Sclerosis Brain-Derived Neurotrophic Factor Breathing Cessation of life Cholera Toxin Data Dependence Disease Disease Progression Environment Failure Future Genetic Models Goals Hypoxia Impairment Injectable Journals Knowledge Laboratories Lead Life Mentors Methods Modeling Motor Motor Neurons Motor output Mutation NADPH Oxidase Neurobiology Neurodegenerative Disorders Neuronal Plasticity Paralysed Pathway interactions Patients Phase Progressive Disease RNA Interference Rattus Reactive Oxygen Species Receptor Activation Research Research Personnel Respiration Respiratory Insufficiency Respiratory physiology Series Serotonin Spinal Structure of phrenic nerve Testing Time Ventilator Work density end stage disease experience improved in vivo interdisciplinary approach motor neuron degeneration nervous system disorder neuron loss neuroregulation notch protein novel strategies novel therapeutics overexpression receptor expression respiratory serotonin receptor superoxide dismutase 1 translational study

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.

项目概要/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拥有独立实验室的成功学术研究员所需的经验关于呼吸的神经控制。威斯康星大学麦迪逊分校拥有许多世界知名的呼吸生理学家每周举办一次呼吸神经生物学研讨会系列和期刊俱乐部系列，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，留在威斯康星大学麦迪逊分校[将使候选人能够受到神经可塑性和呼吸神经生物学领域顶尖研究人员的指导（这是极少数的地方之一）研究这种组合）并获得过渡到独立所需的知识和经验。] 研究：ALS 是一种毁灭性疾病，会导致进行性运动神经元变性和受损呼吸最终导致死亡。尽管呼吸功能不全具有根本重要性，但很少在任何 ALS 模型中进行研究。因此，需要保持足够的通气功能的策略保护生命。该提案的基本目标是确定触发的补偿机制增强呼吸可塑性（间歇性缺氧引起的膈长期促进；pLTF）。增强型可塑性可能使我们能够在呼吸运动神经元死亡模型中恢复膈运动输出，从而保持通气能力。我们建议在呼吸运动神经元死亡大鼠模型中研究 pLTF 包括 ALS 遗传模型（SOD1G93A 大鼠）中遇到的进行性疾病和稳定的、诱导模型（霍乱毒素 B 与皂草素缀合；CTB-SAP）。我们建议使用多学科方法包括：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电机输出； 3) 体内RNAi评估CTB-SAP中AIH诱导的pLTF的细胞机制老鼠； 4) 免疫组织化学方法测定膈运动神经元存活及其表达关键分子。 [三]提出具体目标：1）SOD1G93A表达增加触发代偿 NADPH氧化酶表达增加，从而保持足以表达pLTF的ROS水平； [2) 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 患者出现呼吸功能不全，导致呼吸机依赖或死亡，我们的长期目标是开发新的延迟呼吸运动神经元死亡并增强幸存运动神经元功能能力的策略神经元。在这里，我们将利用增强存活运动神经元功能的机制（AIH 诱导的可塑性）。这些新策略如果成功，可能会指导未来针对患有此病的患者的转化研究呼吸运动神经元死亡，包括 ALS 患者。目前的研究可能具有广泛的影响对 ALS 和其他神经退行性疾病中的非呼吸运动池有好处。