Functional Consequences of Developmental Myosin II Down-regulation in Neurons

描述（由申请人提供）：发育中的神经元经历基因表达的复杂变化，这些变化转化为神经元功能的机制差异。大多数旨在了解轴突延伸机制的研究，因为它们与再生尝试有关，由于技术问题，基于早期胚胎神经元的研究。在拟议的研究中，我解决的变化，发生在轴突延伸的机制，背根神经节感觉神经元从早期到晚期发育阶段的过渡的细胞骨架的基础。机械酶肌球蛋白II已被确定为轴突延伸机制和早期胚胎轴突引导的主要成分。我们的初步数据表明，肌球蛋白II在晚期感觉神经元中下调，并且晚期神经元利用轴突延伸的机制，其独立于机械酶肌球蛋白II用于轴突延伸的功能。此外，与早期神经元不同，晚期神经元在肌球蛋白II依赖性测定中未能进行指导。这项研究的主要目的是确定晚期神经元轴突延伸的机制是否可以通过肌球蛋白II的实验性重新表达而“恢复活力”。这些研究的结果将确定肌球蛋白II在晚期神经元中的重新表达是否有可能将轴突延伸和指导的机制恢复到早期胚胎神经元所利用的机制。从神经系统损伤中恢复是一个重大的社会问题，特别是影响暴力行为发生率较高的人群。这些研究的长期目标是通过确定轴突延伸机制在发育过程中如何变化以及这些变化是否可以逆转以产生具有增加的再生潜力的神经元来提供与促进受损个体的轴突再生相关的信息。越来越多的证据表明，轴突延伸和指导的机制是发育调节。在这一建议中，我试图 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“返老还童”。

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.