Mechanisms Underlying Excitability Regulation of Motoneuron Types in ALS

ALS 运动神经元类型兴奋性调节的机制

• 批准号: 10367137
• 负责人: Sherif M Elbasiouny
• 金额: $ 57.09万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367137
• 关键词: 3-Dimensional; ALS pathology; ALS patients; Amyotrophic Lateral Sclerosis; Anatomy; Cell Death; Cell model; Cells; Cessation of life; Complex; Computer Models; Data; Dementia; Development; Disease; Drug Targeting; Electrophysiology (science); Environment; Event; Exhibits; FDA approved; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Goals; Immunohistochemistry; Ion Channel; Knowledge; Lead; Life; Link; Measures; Mediating; Modeling; Motor Neurons; Mus; Muscle fasciculation; Nerve Degeneration; Neurons; Paralysed; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Prevention; Property; Public Health; Regulation; Riluzole; Role; Severities; Spinal; Stains; Symptoms; Testing; Tweens; Western Blotting; Work; amyotrophic lateral sclerosis therapy; base; effective therapy; excitotoxicity; experimental study; frontotemporal lobar dementia-amyotrophic lateral sclerosis; neurobiotin; neuronal excitability; new therapeutic target; novel; predictive modeling; prevent; reconstruction; theories; therapeutic target

Project Summary/Abstract Multifarious pathologies of amyotrophic lateral sclerosis (ALS) have been studied, yet effective treatments remain elusive. Abnormalities in motoneuron (MN) excitability remain the most tightly linked to disease path- ogenesis. The central hypothesis of this proposal is that these abnormalities are not an epiphenomenon of ALS, but rather an early pathophysiologic event that initiates the events leading to MN death. Paradoxically, both MN HYPER- and HYPO-excitability changes have been seen at various disease stages, in multiple lines of ALS mice. The lack of clarity on what roles hyper- and hypo-excitability changes play (i.e., neuropro- tective or detrimental), and which ion channels underlie these changes, represents a critical barrier to the development of more effective treatments. The rationale for this proposal is that understanding how hypo- excitability mechanisms also contribute to the increasingly unstable MN environment will fill an important gap in knowledge. The working hypotheses of this proposal are that: 1) Hyper- and hypo-excitable changes in MN properties are not mutually exclusive, but can concurrently exist; 2) they represent fluctuations be- tween disease and compensatory mechanisms; 3) their opposing effects cause excitability fluctuations that are initially manageable; but then escalate in magnitude, eventually leading to MN death; and 4) under- standing the ionic mechanisms underlying both hyper- and hypo-excitability changes can lead to drug tar- gets for stabilization of MN excitability to prevent MN death. The hypotheses will be tested via these Aims: Aim 1: Determine the form of motoneuronal excitability dysregulation at symptom onset, A large array of electrical and anatomical cell properties that modulate excitability will be measured in G93A ALS mouse MNs vs. wild-type (WT) MNs. Aim 2: Identify the cellular mechanisms mediating MN hypo-excitability via computational modeling. High- fidelity computer models will analyze interactions of excitability properties; then predict likely mechanisms. Aim 3: Empirically verify model predictions of reduced Kv2.1 channel activation in MNs and cortical neurons. Electrophysiology, immunohistochemistry, and Western blot experiments will assess the activation and ex- pression levels of ion channels in ALS vs. WT MNs at four key disease stages. If verified, these data would provide the first evidence of concurrent hypo- and hyper-excitability within MNs in ALS, thereby providing a novel mechanism of excitability dysregulation in ALS and frontotemporal lobar degeneration dementia (FTD).

项目摘要/摘要 肌萎缩侧索硬化症(ALS)的各种病理机制已被研究，但仍有有效的治疗方法 仍然难以捉摸。运动神经元(MN)兴奋性异常仍然是与疾病途径联系最密切的- 起源。这一提议的中心假设是，这些异常并不是 ALS，而是一种早期的病理生理事件，启动了导致MN死亡的事件。矛盾的是， 在不同的疾病阶段，MN的高兴奋性和低兴奋性变化均可见于多个 ALS小鼠的品系。缺乏关于高兴奋性和低兴奋性变化所扮演的角色的清楚程度(即，神经前体- 保护性的或有害的)，以及哪些离子通道是这些变化的基础，代表了 开发更有效的治疗方法。这项提议的基本原理是，理解如何次要- 兴奋性机制也有助于日益不稳定的MN环境将填补重要的 知识上的差距。这一提议的工作假设是：1)高兴奋性和低兴奋性变化 在MN中，属性不是相互排斥的，而是可以同时存在的；2)它们代表着波动，是- 疾病和代偿机制之间；3)它们的相反作用引起兴奋性波动， 最初是可控的；但随后规模不断扩大，最终导致MN死亡；以及4)在- 坚持高兴奋性和低兴奋性变化背后的离子机制可以导致药物焦油- GET用于稳定MN的兴奋性，以防止MN死亡。这些假说将通过以下目标进行检验： 目的1：确定症状开始时运动神经元兴奋性失调的形式，大量的 将在G93A ALS小鼠身上测量调节兴奋性的电学和解剖学细胞特性 MNS与野生型(WT)MNS。 目的2：通过计算模型确定MN低兴奋性的细胞机制。高- 富达计算机模型将分析兴奋性特性的相互作用；然后预测可能的机制。 目的3：经验性验证模型对MNS和皮质神经元Kv2.1通道激活减少的预测。 电生理学、免疫组织化学和Western印迹实验将评估细胞的激活和释放。 ALS与WT MN在四个关键疾病阶段离子通道的压低水平。 如果得到证实，这些数据将提供MNS中同时存在的低兴奋性和高兴奋性的第一个证据 在肌萎缩侧索硬化症中，从而提供了一种新的肌萎缩侧索硬化症和额颞叶兴奋性失调的机制 退行性痴呆(FTD)。