SURAL NERVE GRAFTS IN FORNIX LESIONS

穹窿病变中的腓肠神经移植物

• 批准号: 3416443
• 负责人: Jeffrey H Kordower
• 金额: $ 13.88万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3416443
• 关键词: Alzheimer's disease; Cebidae; Macaca mulatta; acetylcholine; age difference; aging; amyloid proteins; artificial immunosuppression; autologous transplantation; behavior test; cognition; disease /disorder model; enzyme linked immunosorbent assay; experimental brain lesion; hippocampus; histochemistry /cytochemistry; homologous transplantation; immunocytochemistry; in situ hybridization; nervous system regeneration; nervous system transplantation; neural degeneration; neuroanatomy; neurochemistry; neurofilament proteins; neuronal guidance; neurotrophic factors; prosencephalon

Converging lines of evidence have suggested that cholinergic basal forebrain [CBF] neurons are sensitive to the trophic effects of a number of growth factors including nerve growth factor [NGF] and fibroblast growth factor [FGF]. Furthermore, these neurons require NGF for their survival and phenotypic differentiation. CBF neurons consistently degenerate in Alzheimer's disease (AD). These data, along with the substantial clinical and experimental literature implicating CBF systems in normal cognitive processes, has led to the hypothesis that administration of growth factors such as NGF may prevent the degeneration of CBF neurons in AD. One shortcoming of this contention is the paucity of supporting data gathered in nonhuman primates. This proposal aims to examine the structural and functional consequences of peripheral nerve grafts upon nonhuman primate CBF neurons. Following peripheral nerve transection, Schwann cells which ensheath peripheral nerves begin de novo synthesis of a number of growth factors and neurite promoting molecules including NGF, ciliary neuronotropic factor, brain derived neuronotrophic factor, laminin, and possibly FGF. We have previously demonstrated that peripheral nerve provides trophic and neurite promoting effects upon primate adrenal chromaffin cells following grafting into parkinsonian monkeys. Recently we have demonstrated that axotomized monkey CBF neurons can be rescued following peripheral nerve grafts if the implant precedes neuronal degeneration. Peripheral nerve grafts also invoke a cholinergic sprouting response. The proposed experiments intend to expand upon these latter observations. The long-term trophic and neurite promoting effects of peripheral nerve implants will be assessed and the dependence of these effects upon the continued presence of the graft will be determined. NGF levels produced by the implant will be quantified over time. Possible detrimental effects of peripheral nerve implantation will be determined via in situ hybridization for the beta amyloid precursor protein and with an immunocytochemical analysis of abnormally synthesized cytoskeletal proteins. The ability of aged primate transected nerve to manifest trophic influences upon NGF sensitive cells will also be determine. NGF production in severed peripheral nerves from young and aged monkeys will be compared in vitro and following grafting. The ability of autologous peripheral nerve grafts to prevent experimentally induced CBF neural degeneration in aged monkeys and the ability of such grafts to reverse age-related cognitive dysfunction will also be assessed. These studies will establish whether peripheral nerve grafts are a good donor source for reversing the consequences of basal forebrain degeneration in primates and will shed light on whether this approach is relevant for the treatment of AD.

越来越多的证据表明，胆碱能基础 前脑[CBF]神经元对一些营养作用敏感， 生长因子，包括神经生长因子[NGF]和成纤维细胞生长 因子[FGF]。 此外，这些神经元的生存需要NGF 和表型分化。 CBF神经元持续变性， 阿尔茨海默病（AD）。这些数据，沿着大量的临床试验， 和实验文献暗示CBF系统在正常认知 过程，导致了这样的假设，即生长因子的管理 如NGF可防止AD时CBF神经元的变性。 一 这一论点的缺点是缺乏收集的支持数据 在非人类灵长类动物中。 本提案旨在审查 外周神经移植物对非人灵长类CBF神经元的影响。 在周围神经切断后，包鞘的雪旺细胞， 周围神经开始从头合成许多生长因子， 神经突促进分子包括NGF，睫状神经营养因子， 脑源性神经营养因子，层粘连蛋白，可能还有FGF。 我们有 以前证明，周围神经提供营养和神经突， 移植对灵长类肾上腺嗜铬细胞的促进作用 变成帕金森病猴子 最近，我们已经证明， 猴CBF神经元可以在周围神经移植后被拯救， 植入会导致神经元变性 周围神经移植物还 引起胆碱能发芽反应 拟议的实验旨在 来扩展后面这些观察。 长期营养和 将评估周围神经植入物的神经突促进作用， 这些效应依赖于移植物的持续存在 将被确定。 将对植入物产生的NGF水平进行定量 随着时间周围神经植入术可能产生的不良影响 将通过β淀粉样蛋白前体的原位杂交来确定 蛋白质，并与异常合成的免疫细胞化学分析 细胞骨架蛋白 老年灵长类动物切断神经的能力 对NGF敏感细胞的明显营养影响也将是 决定。 年轻人和老年人周围神经切断后神经生长因子的产生 将在体外和移植后对猴进行比较。 的能力 自体周围神经移植物预防实验性诱发的CBF 老年猴子的神经退化和这种移植物的能力， 还将评估反向年龄相关的认知功能障碍。 这些 研究将确定周围神经移植物是否是一个好的供体 逆转基底前脑退化的后果的来源， 灵长类动物，并将阐明这种方法是否与 治疗AD。