Ischemic Paraplegia: Modulation by Stem Cell Implant

描述（申请人提供）：使用大鼠脊髓缺血模型，我们 已经表明短暂性脊髓缺血的特定间隔导致 中、小型抑制性神经元的选择性变性 腰骶段和突出痉挛性截瘫的发展。 接受胸腹主动脉手术的患者的神经功能缺损相当 已经描述了动脉瘤修复。虽然神经元变性的程度 可以部分地通过缺血周围温度和/或 一旦脊髓神经元的显著群体被 一旦失去，所造成的神经功能缺损是永久性的和不可逆转的。 重要的是，与脊髓机械损伤引起的截瘫相反， 其特征在于降束完整性的部分或完全丧失 在缺血诱导的截瘫后，下行系统显示出长期存活。 这些特点指向一个简单的去抑制机制会计 痉挛性截瘫近年来，备受关注的 一直专注于神经干细胞或培养的神经干细胞的潜在作用 分化的神经元及其在改善 脑或脊髓神经元损伤后的神经功能障碍 神经变性/损伤。这些初步研究清楚地表明， 或脑内移植神经元祖细胞或神经元具有有益的 对多种病理损伤后功能恢复的影响 包括创伤或局部缺血。在目前的研究中，使用大鼠模型， 主动脉闭塞，我们将研究一种可能的治疗潜力， 植入的神经元祖细胞或分化的神经元， 痉挛性截瘫动物运动功能的恢复。此外，本发明还提供了一种方法， 这些实验有助于阐明：i） 短暂缺血后脊髓植入的干细胞或神经元，和ii） 生长因子（神经营养素-3 [NT-3]，脑源性 神经营养因子[BDNF]，胶质细胞源性神经营养因子[GDNF]） 可以调节植入细胞的存活性以及局部 植入细胞和宿主神经元之间的突触发生。从实际 这些研究将系统地解决我们认为 具有基础和临床重要性。因此，替代神经元的能力 选择性地汇集脊髓缺血后丢失的细胞，并调节它们的 在宿主组织中的功能性掺入可能被证明是特别重要的 在开发新的治疗方式的意义， 脊髓缺血导致的截瘫

DESCRIPTION (provided by applicant): Using the rat spinal ischemia model, we have shown that specific intervals of transient spinal ischemia lead to a selective degeneration of small and medium-sized inhibitory neurons in lumbosacral segments and the development of prominent spastic paraplegia. Comparable neurological deficit in patients undergoing thoracoabdominal aortic aneurysm repair has been described. While the extent of neuronal degeneration can partially be manipulated by peri-ischemic temperature and/or pharmacological treatment once a significant population of spinal neurons is lost, the resulting neurological deficit is permanent and irreversible. Importantly, in contrast to spinal mechanical injury-induced paraplegia, which is characterized by a partial or complete loss of descending tracts integrity after ischemia-induced paraplegia, descending systems show long-term survival. These characteristics point into a simple disinhibitory mechanism accounting for the presence of spastic paraplegia. In recent years a significant attention has been focused on a potential role of neuronal stem cells or cultured differentiated neurons and their therapeutic potentials in ameliorating neurological dysfunction after brain or spinal neuronal neurodegeneration/injury. These initial studies clearly show that intraspinal or intracerebral grafting of neuronal progenitors or neurons have a beneficial effect on recovery of function after a variety of pathological insults including trauma or ischemia. In the present studies, using a rat model of aortic occlusion, we will examine a possible therapeutic potential of spinally implanted neuronal progenitors or differentiated neurons as assessed by the recovery of motor function in animals with spastic paraplegia. In addition, these experiments serve to shed light upon: i) the fate and differentiation of spinally implanted stem cells or neurons after transient ischemia, and, ii) characterization of growth factors (neurotrophin-3 [NT-3], brain-derived neurotrophic factor [BDNF], glial cell line-derived neurotrophic factor [GDNF]) that may modulate survivability of implanted cells as well as local synaptogenesis between implanted cells and host neurons. From a practical standpoint, these studies will systematically address issues which we believe have both basic and clinical importance. Thus, the ability to replace neuronal pools selectively that were lost after spinal ischemia and modulate their functional incorporation in the host tissue may prove to be of particular significance in developing novel therapeutic modalities for managing spinal-ischemia-induced paraplegia.