Molecular Pathways Controlling Respiratory Motor Neuron Formation and Function

控制呼吸运动神经元形成和功能的分子途径

• 批准号: 8965412
• 负责人: BENNETT G NOVITCH
• 金额: $ 32.99万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965412
• 关键词: Address; Amyotrophic Lateral Sclerosis; Autonomic ganglion; Autonomic nervous system; Axon; Birth; Brain Stem; Breathing; Cause of Death; Cells; Cessation of life; Characteristics; Defect; Detection; Development; Disease; Fetal Development; Fiber; Functional disorder; Future; Genes; Growth; Health; Hereditary Disease; Hypercapnic respiratory failure; In Situ; Injection of therapeutic agent; Injury; Limb structure; Location; Messenger RNA; Methods; Molecular; Motor; Motor Activity; Motor Neurons; Movement; Muscle; Neurodegenerative Disorders; Neurons; Pathway interactions; Play; Population; Positioning Attribute; Process; Research; Respiration; Respiratory Diaphragm; Respiratory Muscles; Respiratory physiology; Role; Sleep Apnea Syndromes; Spinal; Spinal Cord; Spinal Muscular Atrophy; Spinal cord damage; Subgroup; Synapses; System; Therapeutic; Time; Tracer; Transgenic Organisms; Work; base; genetic manipulation; insight; mutant; nerve supply; nervous system disorder; neuron loss; novel; organizational structure; programs; repaired; research study; respiratory; respiratory distress syndrome; segregation; transcription factor

 DESCRIPTION (provided by applicant): Breathing is the most essential of our motor activities that starts at birth and persists until death. At the core of this vital function are respiratory mtor neurons (MNs) in the spinal cord that innervate distinct muscle targets such as the diaphragm, intercostals, and abdominals to produce alternating inspiratory and expiratory movements. These activities are principally driven by descending inputs provided by rhythm generating neurons in the brainstem that selectively form monosynaptic synapses with respiratory MNs while avoiding other MN classes. Defects in respiratory motor circuit formation can result in a variety of breathing disorders ranging from sleep apneas to potentially fatal respiratory distress syndromes. Moreover, respiratory motor loss or dysfunction is the primary cause of death in many neurodegenerative diseases and traumatic injuries. Despite the importance of respiratory MNs function for survival, remarkably little is known about the developmental origins of these cells and the mechanisms that guide their assembly into functional motor circuits. In our previous work, we identified a novel population of spinal MNs termed the hypaxial motor column (HMC) associated with innervation of body wall muscles and the diaphragm. We further discovered that HMC MN formation is actively suppressed by the transcription factor Foxp1. In Foxp1 mutants, MNs acquire HMC characteristics and display exuberant growth towards respiratory muscle targets. From these findings we conclude first that respiratory MNs are likely the mature derivatives of the HMC, and second that Foxp1 plays a critical role suppressing the program of respiratory MN formation. We build upon these observations to elucidate the developmental program through which respiratory motor circuits are constructed. In Aim 1, we will examine the organizational features of the HMC, particularly its subdivision into pools associated with inspiratory and expiratory motor activities. We will also examine the function of transcription factors that our preliminary studies show are reciprocally expressed by inspiratory and expiratory MN subpopulations and thus candidates for conveying these MN activities. Lastly, in Aim 2, we will examine how descending respiratory premotor inputs from the brainstem respond to changes in either the molecular identity of different MN subtypes or their settling position within the spinal cord in terms of axonal targeting and selection of synaptic partners. Through these studies we hope to gain fundamental insights into how respiratory motor circuits are constructed and the organizational principles of descending pathways in the CNS. This information will be invaluable for understanding the basis of disorders that impair respiratory functions, and future efforts to evoke repair of the diseased or damaged spinal cord by harnessing these developmental mechanisms.

 描述（由适用提供）：呼吸是我们运动活动中最重要的，该活动始于出生，一直持续到死亡。这一重要功能的核心是脊髓中的呼吸道MTOR神经元（MN），这些神经元（MNS）支配了不同的肌肉靶标，例如膜片，骨间和腹部，以产生替代的灵感和到期运动。这些活动主要是由节奏在脑干中产生神经元提供的降序输入驱动的，这些神经元在脑干中有选择地形成单突触突触，同时避免了其他MN类。呼吸运动电路形成的缺陷会导致各种呼吸障碍，从睡眠呼吸暂停到潜在的致命呼吸窘迫综合征。此外，呼吸运动损失或功能障碍是许多神经退行性疾病和创伤性损伤的主要原因。尽管呼吸道MNS功能对于生存具有重要意义，但对于这些细胞的发育起源以及将其组装引导成功能性运动电路的机制知之甚少。在我们以前的工作中，我们确定了与体壁肌肉和隔膜神经相关的高轴运动柱（HMC）的新型脊髓MN人群。我们进一步发现，HMC MN的形成被转录因子FOXP1积极抑制。在FOXP1突变体中，MNS获得了HMC特征并显示出呼吸肌靶标的旺盛生长。从这些发现中，我们首先包含呼吸道MN可能是HMC的成熟衍生物，其次是FOXP1起着抑制呼吸道MN形成程序的关键作用。我们基于这些观察结果，以阐明构建呼吸运动电路的发展计划。在AIM 1中，我们将研究HMC的组织特征，尤其是其细分为与灵感和到期运动活动相关的池。我们还将研究我们的初步研究表明的转录因子的功能，通过灵感和到期的MN亚群相互表示，从而传达了这些MN活动。最后，在AIM 2中，我们将研究来自脑干的下降呼吸前输入如何应对不同MN亚型的分子身份的变化，或者在轴突靶向和选择突触伙伴的角度方面的分子身份或它们在脊髓中的固定位置。通过这些研究，我们希望获得有关如何构建呼吸电路和中枢神经系统下降途径的组织原理的基本见解。这些信息对于理解损害呼吸功能的疾病的基础以及通过利用这些发育机制来唤起患病或受损的脊髓修复的努力将是无价的。