Functional Consequences of Developmental Myosin II Down-regulation in Neurons

神经元中发育性肌球蛋白 II 下调的功能后果

• 批准号: 7883974
• 负责人: Steven L Jones
• 金额: $ 3.89万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883974
• 关键词: Address; Adult; Affect; Afferent Neurons; Axon; Biological Assay; Biological Models; Biology; Cells; Cellular biology; Communication; Complex; Data; Dendrites; Development; Developmental Biology; Down-Regulation; Embryo; Enzymes; Exhibits; Failure; Gene Expression; Goals; Growth Cones; Incidence; Individual; Injury; Lead; Myosin Type II; Natural regeneration; Nerve Regeneration; Nervous system structure; Neurons; Population; Process; Recovery; Research; Research Design; Spinal Ganglia; Staging; Therapeutic; Translating; Violence; axon regeneration; base; early embryonic stage; injured; neurochemistry; neuronal guidance; regenerative

DESCRIPTION (provided by applicant): Developing neurons undergo complex changes in gene expression that translate into mechanistic differences in how the neuron functions. The majority of studies aimed at understanding the mechanisms of axon extension, as they relate to regenerative attempts, are based on studies of early embryonic neurons due to technical issues. In the proposed research I address the cytoskeletal basis of changes that occur in the mechanism of axon extension as dorsal root ganglion sensory neurons transition from early to late developmental stages. The mechano-enzyme myosin II has been determined to be a major component of the mechanism of axon extension and guidance of early embryonic axons. Our preliminary data demonstrate that myosin II is down- regulated in late stage sensory neurons, and that late stage neurons utilize a mechanism of axon extension independent on the function of the mechano-enzyme myosin II for axon extension. In addition, late stage neurons fail to undergo guidance in myosin II-dependent assays, unlike early stage neurons. The major aim of the research proposed is to determine if the mechanism of axon extension in late stage neurons can be "rejuvenated" by experimental re-expression of myosin II. The results of these studies will determine whether re-expression of myosin II in late stage neurons has the potential to revert the mechanisms of axon extension and guidance to those utilized by early embryonic neurons. Recovery from Injury to the nervous system is a major societal issue, particularly affecting populations with higher incidence of violent behavior. The long term goal of these studies is to provide information relevant to the promotion of axon regeneration in injured individuals by determining how the mechanism of axon extension changes during development and whether these changes can be reverted to generate neurons with increased regenerative potential. Mounting evidence indicates that the mechanisms of axon extension and guidance are developmentally regulated. In this proposal I seek to elucidate the functional consequences of the developmental downregulation of myosin II expression in sensory neurons and determine if older neurons can be "rejuvenated" by re-expression of myosin II.

描述（由申请人提供）：发展神经元的基因表达发生复杂的变化，这些变化转化为神经元功能的机理差异。大多数旨在理解与再生尝试相关的轴突扩展机制的研究是基于由于技术问题而对早期胚胎神经元的研究。在拟议的研究中，我介绍了轴突延伸机理中发生变化的细胞骨架基础，因为背根神经节感觉神经元从早期发育阶段转变。机械 - 酶肌球蛋白II已被确定为轴突延伸机理的主要组成部分和早期胚胎轴突的引导。我们的初步数据表明，肌球蛋白II在晚期感觉神经元中受到调节，并且晚期神经元使用轴突扩展机理独立于机械酶肌球蛋白II的功能进行轴突扩展。此外，与早期神经元不同，晚期神经元未能在肌球蛋白II依赖性测定中进行指导。该研究提出的主要目的是确定通过肌球蛋白II的实验重新表达后期神经元中轴突延伸的机理。这些研究的结果将确定在晚期神经元中肌球蛋白II的重新表达是否有可能恢复轴突延伸的机理和向早期胚胎神经元使用的轴突扩展的机理。从伤害到神经系统的恢复是一个主要的社会问题，尤其是影响暴力行为发生率更高的人群。这些研究的长期目标是通过确定在发育过程中轴突延伸的机制如何变化以及是否可以恢复具有增长潜力的神经元，提供与受伤个体轴突再生有关的信息。越来越多的证据表明，轴突扩展和指导的机制受到发展的调节。在这个建议中，我寻求 阐明肌球蛋白II表达的发育下调的功能后果 感觉神经元并确定是否可以通过肌球蛋白II的重新表达来“恢复”较老的神经元。