Peripheral Territory Establishment By Zebrafish Somatosensory Neurons

斑马鱼体感神经元的外周区域建立

基本信息

批准号：
9521182
负责人：
Alvaro Sagasti
金额：
$ 2.92万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9521182
关键词：
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Actins Address Adopted Adult Anatomy Animals Architecture Axon Binding Biochemical Biological Assay Cells Charcot-Marie-Tooth Disease Collagen Complex Cutaneous Cytoskeleton Data Defect Development Diabetes Mellitus Dimensions Disease EXT2 gene Eating Embryo Embryology Embryonic Development Enzymes Event Fishes Glycoproteins Goals Growth Heparan Sulfate Proteoglycan Heparitin Sulfate Human Image Inherited Injury Instruction Invertebrates Larva Length Leukocytes Light Maintenance Mammals Modeling Molecular Morphogenesis Morphology Mosaicism Natural regeneration Nature Nervous system structure Neuroglia Neurons Optics Peripheral Peripheral Nervous System Diseases Phagocytes Phagocytosis Phosphatidylinositols Play Presynaptic Terminals Process Production Protein Tyrosine Phosphatase Reagent Regulation Role Sensory Signal Transduction Site Skin Specificity Stereotyping Stimulus Structure Syndrome System Techniques Testing Tissues Touch sensation Transgenic Organisms Traumatic injury Wallerian Degeneration Zebrafish apical membrane axon growth axon injury axon regeneration axonal degeneration cell behavior chronic pain effective therapy experimental study gain of function in utero injured insight loss of function nerve supply nervous system disorder painful neuropathy programs public health relevance receptor repaired seal somatosensory three dimensional structure time use tool

项目摘要

DESCRIPTION (provided by applicant): Somatosensory neurons project peripheral axons to the skin early in development to detect touch stimuli. Although the cutaneous terminals of these axons are often a proportionally small component of the total peripheral axon length, they are critical for function, since they are the sites where touch stimuli are first detected. Cutaneous axon endings are particularly vulnerable to damage by injury, diabetes, and inherited syndromes, notably Charcot-Marie-Tooth diseases. All of these conditions cause debilitating peripheral neuropathies characterized by chronic pain or the inability to sense touch. Characterizing how cutaneous sensory endings are formed, maintained, and respond to injury is thus essential for understanding these conditions and developing effective treatments. We have developed a larval zebrafish model to study the development of somatosensory peripheral axons and the skin cells that they innervate. Because zebrafish larvae are fertilized externally, develop rapidly, and are optically clear, the zebrafish somatosensory system offers unparalleled experimental access to the early stages of skin innervation. By contrast, studying these cutaneous sensory terminals in mammals is challenging, since they develop in utero and their complete three-dimensional structures are difficult to visualize. Most anatomical and molecular features of somatosensory axon territories in the skin are well conserved from fish to mammals, making zebrafish a relevant model for uncovering potential disease mechanisms. Our studies of the past few years have revealed that skin cells play several critical roles in the development, repair and function of somatosensory axon terminals in the skin. The goal of this proposal is to identify and characterize the molecular dialogues between axons and skin cells that regulate the establishment and maintenance of somatosensory axon territories. Using a unique and powerful set of molecular techniques and transgenic tools that we have developed in recent years, we will investigate three questions about the nature of axon/skin interactions during specific stages of somatosensory neuron ontogeny. First, how are sensory axons guided to the skin? Second, once in the skin how do axons become structurally associated with skin cells? And third, how does the skin respond to axon damage and contribute to repair? We will address these questions with a powerful combination of live imaging, embryology and molecular perturbations. Collectively, these studies will provide the first molecular insight into the regulation of several newly discovered functions of skin cells in the development and maintenance of the somatosensory system.

描述（由申请人提供）：体感神经元在发育中早期向皮肤的外周轴突进行触摸刺激。尽管这些轴突的皮肤末端通常是总周围轴突长度的成比例小部分，但它们对于功能至关重要，因为它们是首先检测到触摸刺激的位点。皮肤轴突末端特别容易受到伤害，糖尿病和遗传综合症的损害，尤其是charcot-marie-marie-tooth疾病。所有这些疾病会导致衰弱的周围神经病，其特征是慢性疼痛或无法接触。因此，表征如何形成，维持，维持和应对伤害的皮肤感觉结局对于理解这些疾病和发展有效治疗至关重要。我们已经开发了一个幼虫斑马鱼模型，以研究体感外周轴突和它们支配的皮肤细胞的发展。由于斑马鱼幼虫在外部受精，迅速发育并在光学上清除，因此斑马鱼体感系统提供了无与伦比的实验性进入皮肤神经支配的早期阶段。相比之下，研究这些皮肤的感觉终端在哺乳动物中是具有挑战性的，因为它们在子宫内发展，并且它们的完整三维结构很难可视化。皮肤体感轴突领土的大多数解剖学和分子特征从鱼到哺乳动物都得到了很好的保守，使斑马鱼成为发现潜在疾病机制的相关模型。我们对过去几年的研究表明，皮肤细胞在皮肤中体感轴突末端的发育，修复和功能中起着几个关键作用。该建议的目的是识别和表征调节体感轴突领土建立和维护的轴突和皮肤细胞之间的分子对话。使用近年来我们开发的一组独特而强大的分子技术和转基因工具，我们将研究三个问题，以了解体感神经元的特定阶段的轴突/皮肤相互作用的性质。首先，感觉轴突如何引导到皮肤？其次，一次在皮肤中，轴突如何在结构上与皮肤细胞相关联？第三，皮肤如何应对轴突损伤并有助于修复？我们将通过实时成像，胚胎学和分子扰动的强大组合来解决这些问题。总的来说，这些研究将提供第一个分子见解，以调节几个新发现的皮肤细胞在体感系统的开发和维护中的功能。