Hox genes in the development of respiratory circuits

Hox 基因在呼吸回路发育中的作用

基本信息

批准号：
8738732
负责人：
Polyxeni Philippidou
金额：
$ 8.64万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-29 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738732
关键词：
Address Affect Amyotrophic Lateral Sclerosis Award Behavior Biological Assay Biological Neural Networks Birth Brain Stem Breathing Cause of Death Cell Nucleus Central Sleep Apnea Cervical spinal cord structure Dasen Defect Development Disease Ensure Environment Equipment Excision Exhibits Extinction (Psychology)Frequencies Functional disorder Gene Expression Gene Expression Profiling Gene Targeting Genes Genetic Goals Individual Interneurons Label Lead Mammals Maps Medical center Mentors Methods Molecular Molecular Genetics Motor Motor Neurons Movement Mus Muscle Muscle Contraction Muscular Dystrophies Neurons Neurosciences Pathway interactions Perinatal Phase Physiological Plethysmography Population Positioning Attribute Proteins Rabies virus Research Research Personnel Respiration Disorders Respiratory Diaphragm Respiratory Failure Respiratory physiology Role Sleep Apnea Syndromes Source Specificity Spinal Spinal Cord Synapses System Techniques Tissue-Specific Gene Expression Training Universities Vertebrates Viral Virus Work alternative treatment axon guidance base career development cell type experience improved in vivo insight motor neuron development nerve supply new therapeutic target protein expression public health relevance research study respiratory

项目摘要

DESCRIPTION (provided by candidate): Breathing is a vital motor behavior that relies on diaphragm muscle contractions in mammals. The frequency and amplitude of breathing movements is controlled by neural networks residing in the brainstem and spinal cord. Degeneration of these networks leads to respiratory disorders, such as central sleep apneas, and, eventually, respiratory failure. My long term goal is to uncover the basic principles underlying respiratory circuit assembly so that we can begin to consider alternative treatment methods for respiratory dysfunction. A conundrum in the study of respiratory neural networks is that while significant progress has been made in defining the rhythmogenic circuits in the brain stem, the developmental origins, molecular identity and connectivity of spinal cord respiratory neurons remain unknown. Overall, the proposed research aims to define the genetic and molecular pathways that underlie spinal respiratory network assembly. We have recently demonstrated that the development of phrenic motor column (PMC) neurons in the cervical spinal cord, which innervate the diaphragm, requires the sustained activity of Hox5 genes. Mice lacking Hox5 genes in motor neurons (MNs) die of respiratory failure at birth and exhibit defects in multiple aspects of PMC identity, including clustering, axon guidance and diaphragm innervation. During the mentored part of this award, the role of Hox5 genes in PMC MNs will be further explored. Differential gene expression analysis will be carried out in order to identify genes acting downstream of Hox5 proteins to regulate distinct aspects of PMC development (Aim 1). Additionally, transsynaptic virus-based tracing approaches will be implored to examine how Hox5 removal from MNs affects the establishment of premotor inputs to the PMC (Aim 2). During the independent phase of the award, the role of Hox genes and their downstream targets in spinal cord respiratory interneuron development and connectivity will be examined (Aim 3). Addressing this question will rely heavily on genetic approaches, transsynaptic circuit labeling techniques and physiological respiratory assays, in which expertise will be acquired during the K99 phase. The mentored part of the research will be performed at the Dasen and Fishell labs at NYU Medical Center, an outstanding research environment that will provide all the equipment and facilities required for the proposed experiments. In addition, Dr. Kinkead at Laval University will act as a consultant and will provide training in the technique of plethysmography. I have assembled a committee who will oversee my progress and provide technical and intellectual input during the mentored part of the award. My previous experience in molecular neuroscience, in combination with a rigorous training plan, will ensure the successful completion of the proposed research aims, while the career development activities during the K99 phase of the award will facilitate a smooth transition to an independent position.

描述（由考生提供）：呼吸是哺乳动物的一种重要运动行为，依赖于膈肌收缩。呼吸运动的频率和幅度由脑干和脊髓中的神经网络控制。这些网络的退化会导致呼吸系统疾病，例如中枢性睡眠呼吸暂停，并最终导致呼吸衰竭。我的长期目标是揭示呼吸回路组装的基本原理，以便我们可以开始考虑呼吸功能障碍的替代治疗方法。呼吸神经网络研究的一个难题是，虽然在定义脑干节律性回路方面取得了重大进展，但脊髓呼吸神经元的发育起源、分子身份和连接性仍然未知。总体而言，拟议的研究旨在定义脊髓呼吸网络组装基础的遗传和分子途径。我们最近证明，颈脊髓中支配膈肌的膈运动柱（PMC）神经元的发育需要 Hox5 基因的持续活性。运动神经元 (MN) 中缺乏 Hox5 基因的小鼠在出生时死于呼吸衰竭，并在 PMC 身份的多个方面表现出缺陷，包括聚类、轴突引导和膈肌神经支配。在该奖项的指导部分中，将进一步探讨 Hox5 基因在 PMC MN 中的作用。将进行差异基因表达分析，以确定作用于 Hox5 蛋白下游的基因，以调节 PMC 发育的不同方面（目标 1）。此外，基于跨突触病毒的追踪方法将被用来研究从 MN 中去除 Hox5 如何影响 PMC 运动前输入的建立（目标 2）。在该奖项的独立阶段，将检查 Hox 基因及其下游靶标在脊髓呼吸中间神经元发育和连接中的作用（目标 3）。解决这个问题将在很大程度上依赖于遗传方法、突触环路标记技术和生理呼吸测定，其中的专业知识将在 K99 阶段获得。该研究的指导部分将在纽约大学医学中心的 Dasen 和 Fishell 实验室进行，这是一个出色的研究环境，将提供拟议实验所需的所有设备和设施。此外，拉瓦尔大学的金基德博士将担任顾问，并提供体积描记法技术的培训。我组建了一个委员会，负责监督我的进展，并在奖项的指导部分提供技术和智力投入。我之前在分子神经科学方面的经验，加上严格的培训计划，将确保成功完成拟议的研究目标，而该奖项K99阶段的职业发展活动将有助于顺利过渡到独立职位。