MECHANISMS OF CORTICOSPINAL TRACT REGENERATION

描述（由申请人提供）： 皮质脊髓束（CST）对于身体的自主控制是必不可少的。 远端肌肉组织缺乏有效的治疗方法来恢复这一途径 对脊髓损伤的受害者来说是毁灭性的后果。在 在动物研究中，已经在使受损的CST轴突 通过改变细胞外环境来再生，尽管到目前为止， 生长通过损伤部位的纤维数量仍然很小。最近 我们实验室的实验表明，嘌呤核苷肌苷激活一种 神经元中的细胞内机制，导致广泛的轴突生长。在 单侧皮质脊髓束横断成年大鼠，肌苷 注入到正常的感觉运动，皮质诱导未受伤的皮质 锥体细胞长出轴突侧支，穿过去神经支配的神经， 脊髓的一半，在某些情况下， 突触根据这些意见，目标1将审查 横切的皮质脊髓束轴突可以通过治疗诱导再生， 他们的细胞体与肌苷，而在同一时间使用神经干细胞 和/或嗅鞘细胞，以提供在嗅鞘细胞处的细胞环境。 损伤部位有利于轴突生长。在目标2中，我们将逆向标记 大鼠感觉运动皮层的锥体细胞，然后， 经过各种实验处理后，使用荧光激活细胞分选 分离出产生皮质脊髓束的神经元通过 使用微阵列（基因芯片），我们将确定与轴突相关的基因 生长、生长锥导向和皮质脊髓束的其他方面 再生这些研究将提供生物学方面的基本信息， 调节CST轴突生长的机制，将帮助我们开发新的 在这条通路受损后恢复功能的方法。

DESCRIPTION (provided by applicant): The corticospinal tract (CST) is essential for voluntary control of the body's distal musculature. The absence of effective treatments to restore this pathway after injury has devastating consequences for victims of spinal cord damage. In animal studies, progress has been made in getting injured CST axons to regenerate by altering the extracellular environment, though to date, the number of fibers that grow past an injury site remains small. Recent experiments in our lab show that the purine nucleoside inosine activates an intracellular mechanism in neurons that leads to extensive axon growth. In mature rats with unilateral transections of the corticospinal tract, inosine infused into the normal sensorimotor, cortex induced uninjured cortical pyramidal cells to sprout axon collaterals that crossed over to the denervated half of the spinal cord, and in some instances formed anatomically appropriate synapses. Following up on these observations, Aim 1 will examine whether transected corticospinal tract axons can be induced to regenerate by treating their cell bodies with inosine, while at the same time using neural stem cells and/or olfactory ensheathing cells to provide a cellular environment at the lesion site conducive to axonal growth. In Aim 2 we will retrogradely label the pyramidal cells of the rat's sensorimotor cortex prior to surgery and then, after various experimental treatments, use fluorescence-activated cell sorting to isolate the neurons that give rise to the corticospinal tract. Through the use of microarrays (gene chips), we will identify genes associated with axon growth, growth cone guidance, and other aspects of corticospinal tract regeneration. These studies will provide basic information on the biological mechanisms that regulate CST axon growth and will help us develop novel approaches to restoring, function after injury to this pathway.