Genetic Analysis of Peripheral Nerve Development

周围神经发育的遗传分析

• 批准号: 8462303
• 负责人: Bruce H Appel
• 金额: $ 31.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462303
• 关键词: Adult; Affect; Axon; Behavior; Biological Models; Cells; Childhood; Color; Data; Development; Disease; Dynein ATPase; Embryonic Development; Erinaceidae; Failure; Functional disorder; Genes; Genetic; Goals; Health; Image; Interneurons; Knowledge; Learning; Maintenance; Molecular; Motor; Movement; Muscle; Muscle Weakness; Mutation; Nerve; Nervous system structure; Neuraxis; Neuroglia; Notch Signaling Pathway; Pain; Perineurial Cell; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Proteins; Role; Schwann Cells; Signal Transduction; Specific qualifier value; Spinal Cord; Stimulus; Temperature; Testing; Time; Transgenic Organisms; Vertebrates; Work; Zebrafish; cell type; design; effective therapy; gastrointestinal; gene function; genetic analysis; glial cell development; in vivo; insight; meetings; mutant; myelination; novel; painful neuropathy; research study; therapy design; time use

DESCRIPTION (provided by applicant): The term goal of this project is to produce a comprehensive and detailed understanding of the cellular and molecular mechanisms that guide formation of peripheral nerves in vertebrates. During development, numerous connections are established between the central nervous system (CNS) and the body via peripheral nerves. These nerves are responsible for conveying information in two directions. Some nerves carry signals out of the CNS to the body to control movement and autonomic functions whereas other nerves transmit information about external stimuli from the body to the CNS. Failure to properly form or maintain peripheral nerves results in a large array of peripheral neuropathies that are manifested as, for example, muscle weakness and loss of muscle control, gastrointestinal dysfunction, inability to sense pain or change in temperature and neuropathic pain. Our approach to investigating peripheral nerve development is to create transgenic zebrafish that express fluorescent proteins in different cellular components of peripheral nerves and then combine in vivo, time-lapse imaging with tests of gene function. In preliminary studies we determined that perineurial cells, which form a protective sheath around myelinated motor nerves, originate as glial cells in the ventral spinal cord and that they are essential to motor nerve development. In Specific Aim 1 of this project we will investigate the molecular mechanisms that specify ventral spinal cord precursors to develop as perineurial cells. In Specific Aim 2 we will investigate the roles of perineurial glia and Schwann cells in motor nerve formation. In Specific Aim 3 we will characterize mutations that disrupt Schwann cell development and myelination as a way to identify genes that are necessary for motor nerve formation. Completion of these aims will greatly extend our understanding of both cellular behavior and gene function in peripheral nerve development, facilitating effective design of therapy intended to treat peripheral neuropathies.

描述（由申请人提供）：该项目的长期目标是全面而详细地了解指导脊椎动物周围神经形成的细胞和分子机制。在发育过程中，中枢神经系统（CNS）和身体之间通过外周神经建立了许多连接。这些神经负责向两个方向传递信息。一些神经将信号从CNS传递到身体以控制运动和自主功能，而其他神经将关于外部刺激的信息从身体传递到CNS。不能适当地形成或维持周围神经导致大量周围神经病，其表现为例如肌无力和肌肉控制丧失、胃肠功能障碍、不能感觉疼痛或温度变化和神经性疼痛。我们研究周围神经发育的方法是创造转基因斑马鱼，在周围神经的不同细胞成分中表达荧光蛋白，然后联合收割机结合体内，延时成像和基因功能测试。在初步研究中，我们确定，神经束膜细胞，形成有髓运动神经周围的保护鞘，起源于脊髓腹侧的神经胶质细胞，它们是运动神经发育所必需的。在这个项目的具体目标1中，我们将研究指定腹侧脊髓前体发育为神经束膜细胞的分子机制。在特定目标2中，我们将研究神经束膜胶质细胞和雪旺细胞在运动神经形成中的作用。在具体目标3中，我们将描述破坏雪旺细胞发育和髓鞘形成的突变，以确定运动神经形成所必需的基因。这些目标的完成将极大地扩展我们对周围神经发育中细胞行为和基因功能的理解，促进旨在治疗周围神经病的治疗的有效设计。