MECHANISMS OF CORTICOSPINAL TRACT REGENERATION

描述(由申请人提供)： 皮质脊髓束(CST)对于自主控制身体的 远端肌肉组织。缺乏有效的治疗方法来恢复这一途径 受伤后会对脊髓损伤的受害者造成毁灭性的后果。在……里面 动物研究，在将受伤的CST轴突移植到 通过改变细胞外环境来再生，尽管到目前为止， 通过损伤部位生长的纤维数量仍然很少。近期 我们实验室的实验表明，嘌呤核苷肌苷激活了一种 神经元中导致广泛轴突生长的细胞内机制。在……里面 成年大鼠一侧皮质脊髓束横断，肌苷 注入正常感觉运动，皮质诱导未损伤的皮质 锥体细胞发芽轴突侧支，这些侧支与失神经支配 脊髓的一半，在某些情况下形成的解剖学上合适 突触。根据这些观察结果，目标1将检查 经治疗可诱导横断皮质脊髓束轴突再生 他们的细胞体中含有肌苷，同时使用神经干细胞 和/或嗅鞘细胞来提供细胞环境 病变部位有利于轴突生长。在目标2中，我们将倒退地将 手术前大鼠感觉运动皮质的锥体细胞，然后， 经过各种实验处理后，使用荧光激活细胞分选 分离形成皮质脊髓束的神经元。通过 利用微阵列(基因芯片)，我们将识别与轴突相关的基因 皮质脊髓束的生长、生长锥引导和其他方面 再生。这些研究将提供有关生物的基本信息。 调节CST轴突生长的机制将有助于我们开发新的 这条通路损伤后恢复功能的方法。

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.