Assessment of transplant mediated recovery of function

描述(由申请人提供) 脊髓损伤后神经功能的恢复将 当然需要多方面的遗传学、细胞生物学和药理学 伴随着精确的行为和生理评估的方法。 胎儿神经组织的移植允许一定程度的运动能力 在大鼠和猫脊髓横断后发展时的病变和移植 都是在新生儿身上制造的。我们还证明了转基因的移植物 成纤维细胞改善成人部分损伤后的运动控制。我们的 假说是，移植的细胞可以分泌生物活性分子。 在脊柱横断后提供更大的功能发展或恢复 无论是新生儿还是成年人，因为这些移植物促进了更大的再生。 然而，嫁接后的恢复不太可能完成。药理作用 干预措施，特别是5-羟色胺能激动剂，已被证明 通过移植促进恢复。在这些实验中，我们将继续 药理干预研究以确定其作用机制 这些激动剂的作用是改善脊髓大鼠的功能。我们还将比较 用国产转基因细胞进行胎儿移植 新生儿和成人以确定药理制剂是否起作用 与移植介导的效应协同作用以改善功能 再远一点。替代策略包括联合移植细胞系(RN46A-B14) 将5-羟色胺分泌到腰髓可能会产生更持久的 功能上的改进。我们还将扩大我们的研究范围，包括 既然我们认为儿茶酚胺能激动剂的最佳药理作用 策略可能包括同时刺激5-羟色胺能和去甲肾上腺素能 感受器。在新生儿和成年人身上造成的损伤会改变电路。 营养因子进入新生儿和成人脊髓的实验研究 也可能通过刺激系统轴承的增长来修改电路 合适的受体。脊柱损伤对腰椎神经回路的影响 营养因子的引入是未知的，但在 理解功能恢复的限度和发展的原则性 治疗策略。我们将重点关注下降中的变化 单胺能系统和肽能传入系统及其受体 横断/移植水平和腰椎的结合部位 电源线。小树的下落再生和再生(或萌发) 将用免疫细胞化学方法研究大鼠背根轴突的变化。 它们的受体结合部位的密度将被测量。把这些放在一起 研究应提供有关心力衰竭发病机制的重要信息 对功能的药理刺激，可能导致发展 治疗。

DESCRIPTION (provided by applicant) The restoration of neurological function after injury to the spinal cord will certainly require a multifaceted genetic, cell biological and pharmacological approach accompanied by precise behavioral and physiological evaluation. Transplantation of fetal neural tissue permits some degree of motor competence to develop in rats and cats after spinal transection when the lesion and graft are made in neonates. We have also shown that grafts of genetically modified fibroblasts improve motor control after partial lesions in adults. Our hypothesis is that grafts of cells modified to secrete bioactive molecules will provide greater development or recovery of function after spinal transection in both neonates and adults because these grafts promote greater regeneration. Recovery after grafting, however, is unlikely to be complete. Pharmacological interventions, specifically with serotonergic agonists, have been shown to enhance recovery mediated by transplants. In these experiments we will continue investigation of pharmacological interventions to determine mechanisms by which these agonists act to improve function in spinal rats. We will also compare fetal transplants with transplants of genetically modified cells made in neonates and adults to determine whether pharmacological agents act synergistically with the transplant mediated effects to improve function further. Alternate strategies including co-grafting a cell line (RN46A-B14) that will secrete 5HT into lumbar cord may produce more long-lasting improvement in function. We will also extend our studies to include catecholaminergic agonists since we believe that the optimal pharmacological strategy may include stimulation of both serotonergic and noradrenergic receptors. Lesions made in neonates and in adults modify circuitry. Introduction of trophic factors into the spinal cord of neonates and adults is also likely to modify circuitry by stimulating growth of systems bearing appropriate receptors. The effects on lumbar circuitry of spinal injury and introduction of trophic factors are not known but must be important in understanding the limits on recovery of function and for developing principled therapeutic strategies. We will focus on changes in the descending monoaminergic systems and the peptidergic afferent systems and their receptor binding sites at the level of the transection/transplantation and in lumbar cord. Regeneration of descending and regeneration (or sprouting) of small caliber dorsal root axons will be studied immunocytochemically and changes in density of their receptor binding sites will be measured. Together these studies should provide significant information about mechanisms of pharmacological stimulation of function that may lead to development of therapies.