NEUROTROPHIC FACTOR ANALYSES OF FUNCTIONAL RECOVERY

描述：在帕金森氏病的动物模型和一些 帕金森病患者，多巴胺的神经和副神经移植- 纹状体中丰富的组织已被证明介导功能 恢复。然而，人们对其背后的机制知之甚少。 功能参数的改善。作为一种替代 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，恢复 通过嫁接诱导、营养因子介导、调节 宿主神经系统受损。拟议研究的目标是 通过确定神经营养因子是否 组织移植物或宿主中纹状体系统的产量是一个预测因素 帕金森氏病大鼠模型的功能恢复。这个 研究将集中在脑源性神经营养因子的分析上 (脑源性神经营养因子)、神经营养因子-3(NT-3)、转化生长因子-α(TGFa)，以及 胶质细胞源性神经营养因子(GDNF)。这些神经营养物质 分子已被证明支持多巴胺能神经元在体外和 在体内，并且存在于体内的中纹状体系统中。 此外，申请人实验室的初步工作表明 BDNF及其受体TrkB的mRNAs存在于 正常大鼠纹状体植入后的中脑移植。 这些研究的第一个特定目标是检测神经营养因子。 6-羟基多巴胺(6-OHDA)损毁大鼠脑内的表达 纹状体内植入胎儿中脑移植物。第二 两个特定的目标将直接检验营养因子 由移植产生的通过(A)改善功能缺陷 植入来自新近开发的胎儿中脑组织 缺乏功能性脑源性神经营养因子或NT-3基因的“敲除”小鼠，或(B)通过 向失神经支配的大鼠纹状体内注入营养因子。就地 将在所有实验中使用cna探针杂交来评估 神经营养因子的水平、区域分布和细胞定位 合适的供体移植组织和宿主纹状体中的因子mRNAs 腹侧中脑。营养因子的表达将与 通过改善功能缺陷和神经化学 多巴胺新陈代谢指标。总体而言，拟议的实验 应该会大大增加我们对 6-羟基多巴胺损毁大鼠的纹状体系统。尤其是，这些 研究将提供对塑性和潜在的过程的洞察 与神经功能恢复相关的再生 嫁接和营养因子注射。(摘自《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)