NEUROTROPHIC FACTOR ANALYSES OF FUNCTIONAL RECOVERY

描述：在帕金森病的动物模型中， 帕金森病人，多巴胺的神经和神经旁移植- 丰富的组织进入纹状体已被证明介导功能 复苏 然而，人们对这一现象背后的机制知之甚少。 功能参数的改进。 作为一种替代的 传统观点认为移植物多巴胺分泌是导致 行为和神经化学改善，营养因子假说 移植后功能恢复的研究表明， 通过移植物诱导、营养因子介导、 受损的宿主神经系统 拟议研究的目标是 通过确定神经营养因子 组织移植物或宿主中纹状体系统的产生是预测因子 帕金森病大鼠模型的功能恢复。 的 研究将集中在脑源性神经营养因子的分析 （BDNF）、神经营养因子-3（NT-3）、转化生长因子-α TGF α）和 胶质细胞源性神经营养因子（GDNF）。 这些神经营养 分子已经显示在体外支持多巴胺能神经元， 并且存在于体内的中纹状体系统内。 此外，申请人实验室的初步工作表明， BDNF及其受体trkB的mRNA存在于 正常大鼠纹状体植入后中脑移植。 这些研究的第一个具体目标是检查神经营养因子 在6-羟基多巴胺（6-OHDA）损伤大鼠中， 胎儿中脑移植物的纹状体内植入。 第二 两个具体目标将直接检验营养因子 通过以下方式改善功能缺陷：（a） 植入胎儿中脑组织， 缺乏功能性BDNF或NT-3基因的“敲除”小鼠，或（B）通过 将营养因子注入失神经大鼠纹状体。 原位 cRNA探针的杂交将用于所有实验中，以评价 神经营养因子的水平、区域分布和细胞定位 适当供体移植组织和宿主纹状体中的因子mRNA 和腹侧中脑。 营养因子的表达与 改善功能缺陷以及神经化学 多巴胺代谢的指标 总体而言，拟议的实验 应该大大增加了我们对 6-OHDA损伤大鼠的中纹状体系统。 特别是这些 研究将提供对可塑性的潜在过程的深入了解， 与神经损伤后功能恢复相关的再生 移植和营养因子施用。 (From摘要）

DESCRIPTION: In animal models of Parkinson's disease and in some Parkinsonian patients, neural and paraneural transplants of dopamine- rich tissue into the striatum have been shown to mediate functional recovery. Little is understood, however, of the mechanisms underlying the improvement of functional parameters. As an alternative to the traditional view that graft dopamine secretion accounts for the behavioral and neurochemical improvement, the trophic factor hypothesis of functional recovery following transplantation proposes that recovery occurs through graft-induced, trophic factor-mediated, modulation of injured host neural systems. The goal of the proposed research is to test aspects of this hypothesis by determining if neurotrophic factor production by tissue grafts or host mesostriatal system is a predictor of functional recovery in a rat model of Parkinson's disease. The studies will focus on the analysis of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), transforming growth factor-a TGFa), and glial cell line-derived neurotrophic factor (GDNF). These neurotrophic molecules have been shown to support dopaminergic neurons in vitro and in vivo, and are present within the mesostriatal system in vivo. Moreover, preliminary work from the applicant's laboratory indicates that mRNAs for BDNF and its receptor trkB are present within mesencephalic grafts subsequent to striatal implantation in normal rat. The first specific aim of these studies will examine neurotrophic factor expression in the 6-hydroxydopamine (6-OHDA)-lesioned rat subsequent to intrastriatal implantation of fetal mesencephalic grafts. The second two specific aims will directly test the hypothesis that trophic factors produced by the transplant ameliorate functional deficits by (a) implanting fetal midbrain tissue derived from recently developed "knockout" mice lacking a functional BDNF or NT-3 gene, or (b) by infusing trophic factors, into denervated rat striatum. In situ hybridization of cRNA probes will be used in all experiments to evaluate levels, regional distribution, and cellular localization of neurotrophic factor mRNAs in appropriate donor transplant tissue and in host striatum and ventral mesencephalon. Trophic factor expression will be correlated with amelioration of functional deficits as well as with neurochemical measures of dopamine metabolism. Overall, the proposed experiments should add significantly to our understanding of the properties of the mesostriatal system in 6-OHDA-lesioned rats. In particular, these studies will provide insight into processes underlying plasticity and regeneration associated with functional recovery following neural grafting and trophic factor administration. (From the Abstract)