Mechanisms of inactivity-induced respiratory plasticity

不活动引起的呼吸可塑性机制

• 批准号: 8023774
• 负责人: Tracy L Baker
• 金额: $ 36.74万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8023774
• 关键词: Automobile Driving; Axon; Birth; Brain Stem; Breathing; Cell Nucleus; Cessation of life; Clinical; Data; Disease; Employee Strikes; Ensure; Environmental air flow; Epigenetic Process; Exhibits; Failure; Frequencies; Genetic; Goals; Health; Human; Hypocapnia; Hypoxia; Intervention; Investigation; Life; Literature; Lung; Mammals; Mechanical ventilation; Methods; Modeling; Motor; Motor Neurons; Motor output; Muscle; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroglia; Neuronal Plasticity; Neurons; Neurosciences; Patients; Physiological; Property; Protein Isoforms; Pump; Rattus; Receptor Activation; Reporting; Rivers; Role; Spinal; Spinal Cord Plasticity; Sprague-Dawley Rats; Study models; Synapses; TNF gene; Testing; Ventilator Weaning; Weaning; Work; base; disorder control; effective therapy; insight; novel; receptor; relating to nervous system; respiratory; therapeutic target

DESCRIPTION (provided by applicant): The fundamental hypothesis guiding this proposal is that reduced synaptic inputs to respiratory motor neurons elicits compensatory plasticity, preserving respiratory motor output in a range compatible with life. Our specific goal in the present project period is to investigate cellular mechanisms giving rise to inactivity-induced phrenic motor facilitation (iPMF), a persistent increase in phrenic burst amplitude following prolonged decreases in phrenic neural activity. Two distinct methods of reducing phrenic activity will be studied in anesthetized rats: one that reduces overall activity in the respiratory network (hypocapnia) and another that specifically decreases spinal synaptic inputs to phrenic motor neurons (C2 axon conduction block). The iPMF evoked by these methods exhibits striking similarities, yet may have important differences. Hypocapnia and C2 conduction block both elicit iPMF (i.e., increased amplitude), but only hypocapnia elicits phrenic burst frequency facilitation suggesting the possibility of that iPMF arises from multiple mechanisms depending on whether neural activity was reduced locally versus globally. In this project, we will focus on spinal mechanisms leading to iPMF. Our working model is that reduced synaptic input to phrenic motor neurons stimulates TNF1 release in the phrenic motor nucleus (Aim 1), activating atypical PKC (aPKC) isoforms in or near phrenic motor neurons that give rise to iPMF (Aims 2 and 3). We further propose that iPMF is subject to regulatory constraints, similar to other forms of neuroplasticity. By investigations of a unique sub-strain of Sprague Dawley rats, we will gain critical insights concerning mechanisms that constrain iPMF. In specific, we hypothesize that greater constitutive NMDA-glutamateric receptor activity constrains iPMF in this rat sub-strain (Aim 4), possibly due to genetic or epigenetic factors. Since failure to elicit iPMF may contribute to ventilatory control disorders of importance to human health, such as ventilatory weaning failure following prolonged ventilatory support, differences in constitutive NMDA receptor activity may differentiate patients that successfully wean from ventilatory support versus those that do not. A detailed understanding of cellular cascades giving rise to iPMF is essential to understand the physiological role of this highly novel form of plasticity, and-importantly-to identify promising therapeutic targets for pharmacological interventions to treat respiratory control disorders. PUBLIC HEALTH RELEVANCE: Since breathing is necessary for life, failure to restore adequate breathing after prolonged periods of ventilatory support represents a serious clinical problem. In this project we will investigate a highly novel mechanism of spinal cord plasticity induced by periods of reduced breathing effort. Through a detailed understanding of this mechanism, we hope to understand the neural basis of ventilator weaning failure and to develop treatments for patients that have difficulty resuming unassisted breathing.

描述（由申请人提供）：指导该提议的基本假设是，减少对呼吸运动神经元的突触输入会激发代偿可塑性，将呼吸运动输出保持在与生命相容的范围内。我们在本项目期间的具体目标是研究引起无活动诱导的膈运动易化（iPMF）的细胞机制，这是膈神经活动长期减少后膈爆发振幅的持续增加。将在麻醉大鼠中研究两种不同的减少膈神经活动的方法：一种减少呼吸网络中的总体活动（低碳酸血症），另一种专门减少膈运动神经元的脊髓突触输入（C2轴突传导阻滞）。这些方法诱发的iPMF表现出惊人的相似性，但可能有重要的差异。低碳酸血症和C2传导阻滞都引起iPMF（即，增加的幅度），但只有低碳酸血症elevophrenic爆发频率促进，这表明iPMF可能是由多种机制引起的，这取决于神经活动是局部减少还是整体减少。在这个项目中，我们将专注于导致iPMF的脊柱机制。我们的工作模型是，减少对膈运动神经元的突触输入刺激膈运动核中的TNF 1释放（目的1），激活膈运动神经元中或附近的非典型PKC（aPKC）亚型，产生iPMF（目的2和3）。我们进一步提出，iPMF是受监管的限制，类似于其他形式的神经可塑性。通过对Sprague道利大鼠的一个独特亚系的研究，我们将获得关于限制iPMF的机制的重要见解。具体而言，我们假设，更大的组成型NMDA-受体的活性约束iPMF在这个大鼠亚系（目的4），可能是由于遗传或表观遗传因素。由于未能引起iPMF可能导致对人类健康具有重要意义的排便控制障碍，例如长时间排便支持后的排便断奶失败，因此组成型NMDA受体活性的差异可能会区分成功断奶的患者与未成功断奶的患者。详细了解引起iPMF的细胞级联对于了解这种高度新颖的可塑性形式的生理作用至关重要，并且重要的是，确定有前途的治疗靶点用于治疗呼吸控制障碍的药物干预。 公共卫生关系：由于呼吸是生命所必需的，在长时间的呼吸支持后不能恢复充分的呼吸代表了严重的临床问题。在这个项目中，我们将研究一个高度新颖的机制，脊髓可塑性引起的时期减少呼吸努力。通过对这一机制的详细了解，我们希望了解呼吸机脱机失败的神经基础，并为难以恢复无辅助呼吸的患者开发治疗方法。