Assessment of transplant mediated recovery of function

移植介导的功能恢复评估

• 批准号: 6659342
• 负责人: Marion Murray
• 金额: $ 17.76万
• 依托单位: MCP HAHNEMANN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659342
• 关键词: age difference; cell transplantation; central neural pathway /tract; chordate locomotion; denervation; electromyography; embryo /fetus tissue transplantation; fibroblasts; gene therapy; immunocytochemistry; innervation; laboratory rat; mature animal; nervous system regeneration; nervous system transplantation; neural plasticity; neuromuscular function; neuronal transport; neuropharmacology; neurotransmitter receptor; neurotrophic factors; newborn animals; nonhuman therapy evaluation; rehabilitation; serotonin; spinal cord injury; spinal cord surgery

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.

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 方法伴随着精确的行为和生理评估。 胚胎神经组织移植允许一定程度的运动能力 在大鼠和猫脊髓横断后， 是在新生儿中制造的。我们还证明了转基因植物的移植物 成纤维细胞改善成人部分损伤后的运动控制。我们 一种假说是，经修饰以分泌生物活性分子的细胞移植物将 在脊柱横断后提供更大的功能发育或恢复， 新生儿和成人都是如此，因为这些移植物促进了更大的再生。 然而，移植后的恢复不太可能完全。药理 干预措施，特别是使用β-肾上腺素能激动剂，已经显示， 促进移植介导的恢复。在这些实验中，我们将继续 研究药物干预，以确定 这些激动剂用于改善脊髓大鼠的功能。我们还将比较 胎儿移植与转基因细胞的移植， 新生儿和成人，以确定药物是否起作用 与移植介导的作用协同作用以改善功能 进一步.替代策略，包括共移植细胞系（RN 46 A-B 14） 将5 HT分泌到腰髓中可能产生更持久的 功能改进。我们还将扩大研究范围， 因为我们相信最佳的药理学作用 策略可以包括刺激肾上腺素能和去甲肾上腺素能两者 受体。在新生儿和成人中造成的损伤会改变电路。 将营养因子引入新生儿和成人的脊髓中， 也可能通过刺激系统轴承的增长来修改电路 合适的受体。脊髓损伤对腰椎回路的影响 营养因子引入是未知的，但在 了解功能恢复的局限性， 治疗策略我们将重点关注下降过程中的变化 单胺能系统和肽能传入系统及其受体 横断/移植水平和腰椎中的结合位点 线.下降的再生和小的再生（或发芽） 口径背根轴突将进行免疫细胞化学研究， 将测量它们的受体结合位点的密度。综合这些 研究应提供有关 药理学刺激功能，可能导致发展 治疗