Genetic remodeling of Vagal Afferent Organization

迷走神经传入组织的基因重塑

• 批准号: 6966698
• 负责人: EDWARD A FOX
• 金额: $ 27.91万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966698
• 关键词: afferent nerve; behavior test; brain derived neurotrophic factor; gastrointestinal system; gene expression; genetically modified animals; laboratory mouse; mechanoreceptors; neurogenetics; neurotrophic factors; smooth muscle; vagus nerve

DESCRIPTION (provided by applicant): The vagus or Xth cranial nerve contains both the sensory and motor divisions of the parasympathetic nervous system that regulate the heart, lungs and digestive tract - regulatory activities that are required to sustain life. The sensory division of the vagus is composed of several functional systems, each consisting of a pool of sensory receptors defined by the type of stimulus they transduce (e.g., mechanoreceptor vs. chemoreceptor), by their structure (e.g., the type of mechanoreceptor), and by their location (organ or tissue they innervate). Progress in understanding the structural and functional organization of these vagal sensory channels has to a large extent been elusive. This is mainly because it has been difficult to selectively label or manipulate vagal sensory systems due to their close association with vagal motor, sympathetic, and enteric systems. We propose that a better understanding of the genetic programs that orchestrate development of each vagal sensory channel could provide means to develop tools for selective manipulation of these channels. In the proposed experiments we will first characterize in detail the changes in both the number and the morphology of vagal afferents that innervate the gastrointestinal (Gl) tract in mice with a mutation in either the brain-derived neurotrophic factor (BDNF) gene or the neurotrophin-3 (NT-3) gene. Second, BDNF and NT-3 expression in tissues associated with developing and mature vagal Gl afferents will be mapped in normal mice. Then analysis of the relationship of these expression patterns to the remodeled vagal pathways in the neurotrophin mutants will be used to develop hypotheses about where and when BDNF and NT-3 are essential for development of these pathways. To test these hypotheses, application of the cre-lox recombination system in mice will be used to create conditional BDNF or NT-3 knockouts that are targeted to specific tissues and developmental stages, and then vagal Gl afferent remodeling in these mice will be characterized. Mice with these conditional BDNF or NT-3 knockouts will also be subject to behavioral tests to make an initial assessment of whether this remodeling might affect vagal Gl sensory function. This work will provide novel information about the roles of BDNF and NT-3 in the development of vagal Gl afferent organization. Moreover, it will form an essential foundation for further research on the development of, and the structural and functional organization of, the diverse systems that form the vagal sensorium.

描述（由申请人提供）：迷走神经或XTH颅神经既包含调节心脏，肺和消化道 - 维持生命所需的调节活动的副交感神经系统的感觉和运动师。迷走神经的感觉划分由几个功能系统组成，每个功能系统由它们转导的刺激类型（例如，机械感受器与化学感受器）定义的感觉受体组成，其结构（例如，机械感受器的类型）以及其位置（器官或组织）。在很大程度上难以捉摸，了解这些迷走性感觉渠道的结构和功能组织的进展在很大程度上是难以捉摸的。这主要是因为由于它们与迷走运动，交感神经和肠系统的密切关联，很难选择性地标记或操纵迷走神经感觉系统。我们建议，对每个迷走神经感官渠道的开发的遗传程序有更好的理解可以为开发选择性操纵这些渠道的工具提供手段。在提出的实验中，我们将首先详细介绍迷走神经传入的数量和形态的变化，这些传入的数量和形态在小鼠中支配胃肠道（GL）的数量和形态的变化都具有突变的脑源性神经营养因子（BDNF）基因或神经营养素3（NT-3）基因（NT-3）基因。其次，与发育和成熟的迷走神经传入相关的组织中的BDNF和NT-3表达将在正常小鼠中映射。然后，将使用这些表达模式与神经营养蛋白突变体中重塑的迷走神经途径的关系分析，以开发有关BDNF和NT-3何时以及何时开发这些途径至关重要的假设。为了检验这些假设，将使用CRE-LOX重组系统在小鼠中的应用，以创建针对特定组织和发育阶段的有条件的BDNF或NT-3敲除，然后将在这些小鼠中进行迷走神经GL传入重塑。具有这些条件BDNF或NT-3敲除的小鼠也将经过行为测试，以初步评估这种重塑是否可能影响迷走神经的感觉功能。这项工作将提供有关BDNF和NT-3在流失GL传入组织发展中的作用的新颖信息。此外，它将为进一步研究形成迷走神经传感器的各种系统的发展以及结构和功能组织的进一步研究。