Genetic Analysis of Glial Contribution to Peripheral Nervous System Assembly

胶质细胞对周围神经系统组装的贡献的遗传分析

基本信息

批准号：
8311775
负责人：
Sarah C Kucenas
金额：
$ 32.69万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8311775
关键词：
Ablation Adolescent Adult Affect Axon Behavior Cell Differentiation process Cells Color Coupling Cues Data Defect Degenerative Disorder Development Diagnosis Disease Disease Progression Embryo Ensure Environment Etiology Genes Genetic Goals Human Image Individual Injury Knowledge Left Location Maintenance Malignant Neoplasms Mediating Modeling Molecular Motor Mutate Mutation Myelin Natural regeneration Nerve Nervous system structure Neuraxis Neuroglia Organism Outcome Pathology Perineurial Cell Peripheral Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Pharmacotherapy Phenotype Play Population Proliferating Quality of life Regulation Research Role Schwann Cells Sensory Signal Pathway Signal Transduction Site Specific qualifier value Spinal Cord Staging Structure Time Zebrafish base cell motility cell type extracellular gene function genetic analysis genetic manipulation glial cell development in vivo insight migration mutant nervous system development novel public health relevance therapy design

项目摘要

DESCRIPTION (provided by applicant): Motor nerves play the critical role of shunting information out of the central nervous system to targets in the periphery. Their formation requires the coordinated development of distinct cellular components, including motor axons and the glial cells that ensheathe them. During nervous system construction, these cells must migrate long distances and coordinate their differentiation, ensuring the efficient propagation of electrical information. To better understand, diagnose and treat the many degenerative disorders of the peripheral nervous system, we need to comprehend the cellular and molecular mechanisms that mediate glial interactions along developing nerves and myelin maintenance in juvenile and adult organisms. Zebrafish provide a unique opportunity to directly observe and manipulate cell populations to gain insight into how the PNS is initially established, maintained and behaves during disease. In preliminary studies, we demonstrate that perineurial cells, which form the perineurium, originate as glial cells in the ventral spinal cord, influence Schwann cell development and are essential to motor nerve development. Therefore, in Aim 1 of this project, we will investigate the hypothesis that Schwann cells and perineurial glia reciprocally interact during nerve assembly by utilizing time-lapse imaging and genetic manipulation. In Aim 2, we will characterize two new mutant lines that have defects in perineurial glial development and identify the mutated genes responsible for the phenotypes. Identifying these genes will give us additional information about the molecular mechanisms necessary for PNS formation. Completion of these aims will greatly expand our knowledge of the cellular and molecular mechanisms that mediate peripheral nerve development, facilitating new drug therapies intended to treat peripheral neuropathies. PUBLIC HEALTH RELEVANCE: One or more damaged or dysfunctional components of peripheral nerves can result in peripheral disease or injury. Although the progression of each disorder is unique, the ultimate outcome is a greatly reduced quality of life for the afflicted individual. In this project, we will identify new cellular behaviors and novel genes that are necessary for peripheral nerve assembly and maintenance.

描述（由申请人提供）：运动神经在将信息从中枢神经系统分流到周围目标方面发挥着关键作用。它们的形成需要不同细胞成分的协调发育，包括运动轴突和包裹它们的神经胶质细胞。在神经系统构建过程中，这些细胞必须长距离迁移并协调分化，确保电信息的有效传播。为了更好地理解、诊断和治疗周围神经系统的许多退行性疾病，我们需要了解在幼年和成年生物体中介导神经胶质细胞相互作用以及神经发育和髓磷脂维持的细胞和分子机制。斑马鱼提供了一个独特的机会来直接观察和操纵细胞群，以深入了解三七总皂苷在疾病期间的最初建立、维持和行为。在初步研究中，我们证明形成神经束膜的神经束膜细胞起源于腹侧脊髓中的神经胶质细胞，影响雪旺细胞的发育，并且对运动神经发育至关重要。因此，在该项目的目标 1 中，我们将利用延时成像和基因操作来研究雪旺细胞和神经周围胶质细胞在神经组装过程中相互作用的假设。在目标 2 中，我们将表征两个在神经周围神经胶质发育中存在缺陷的新突变系，并鉴定导致表型的突变基因。识别这些基因将为我们提供有关三七总皂苷形成所需分子机制的更多信息。这些目标的完成将极大地扩展我们对介导周围神经发育的细胞和分子机制的了解，促进旨在治疗周围神经病的新药物疗法。公共卫生相关性：周围神经的一种或多种受损或功能障碍可能导致周围疾病或损伤。尽管每种疾病的进展都是独特的，但最终的结果是患者的生活质量大大降低。在这个项目中，我们将鉴定周围神经组装和维护所必需的新细胞行为和新基因。