REGNERATION IN THE AGED AND INJURED DOPAMINE SYSTEM

中脑腹侧的多巴胺(DA)神经元 在啮齿动物、猴子和人类中，纹状体表现出与年龄相关的恶化。 黑质纹状体DA系统的严重退化产生了运动 帕金森氏症人类特有的功能障碍。近期 我们实验室的证据表明，胚胎大鼠DA的暴露 从移植的周围神经获得可扩散产物的神经元 培养的雪旺细胞可提高存活率和突起 这些DA神经元在培养中生长。DA的类似增强 胚胎DA神经元联合培养可获得神经元的存活和生长。 周围神经节段移植于DA耗竭的纹状体内 老鼠。此外，周围神经的脑室内植入 25月龄大鼠节段上调酪氨酸羟化酶(TH) 在植入物同侧的整个黑质纹状体系统染色。 最后，我们分离出了雪旺细胞的低分子量组分。 含有DA神经元存活和促进生长的条件培养液 活性，在本申请中称为多巴胺神经营养因子 (DNTF)。目前的提案旨在扩大这些初步调查结果 S将记录是否补偿性增长和/或活动 幼年和老年大鼠黑质纹状体DA神经元的诱导 通过接触产品对DA系统造成不同程度的损害 移植的雪旺细胞或脑室内输注条件性 中组分(DNTF)。由于识别DNTF正在进行中， 不完全，我们还将测试DNTF的相对效果，以促进 DA神经元存活和生长与四种已知生长因子的比较 它们对培养的DA的活性有积极的影响 神经元：碱性成纤维细胞生长因子、神经营养因子、胰岛素样生长因子-1和表皮生长因子。文化和动物研究都将 收集有关因素引起的补偿幅度的信息 发展援助系统的变化，与发展援助的数量和地点的关系 DA神经元生长的细胞机制研究进展 升职。来自行为测量的证据，免疫细胞化学 形态、神经递质和代谢物分析以及 THmRNA的表达将结合起来解决这些感兴趣的问题。在……里面 此外，我们将继续我们的初步研究结果，即增强了 外周共同移植的胚胎DA神经元移植 神经，通过比较胚胎DA神经元移植和混合移植 青年和老年大鼠，短期(3周)或长期(12 月)黑质纹状体DA通路的损害。的进一步研究 雪旺细胞及其产物作为生存和生长的来源- 促进DA神经元的活动可能为生物学提供见解 衰老影响中枢神经系统的机制 可塑性，以及对实验的令人兴奋的影响 老龄化和帕金森氏病的治疗。

Dopamine (DA) neurons of the ventral mesencephalon which innervate the striatum show age-related deterioration in rodents, monkeys and humans. Severe degeneration of this nigrostriatal DA system yields the motor dysfunctions characteristic of Parkinson's disease in humans. Recent evidence from our laboratory indicates that exposure of embryonic rat DA neurons to diffusible products derived from an explanted peripheral nerve segment, or cultured Schwann cells, enhances survival and neurite outgrowth of these DA neurons in culture. Similar enhancement of DA neuron survival and growth is obtained when embryonic DA neurons are co- grafted with a peripheral nerve segment to the striatum of DA-depleted rats. In addition, intraventricular implantation of the peripheral nerve segment in 25 month old rats upregulates tyrosine hydroxylase (TH) staining in the entire nigrostriatal system ipsilateral to the implant. Finally, we have isolated a low molecular weigh fraction of Schwann cell conditioned medium that contains DA neuron survival and growth-promoting activity, referred to in this application as dopamine neurotrophic factor (DNTF). The current proposal seeks to extend these preliminary finding s to document whether compensatory growth and/or activity of nigrostriatal DA neurons can be induced in young adult and aging rats with variable degrees of damage to the DA system via exposure to products of grafted Schwann cells or intraventricular infusion of the conditioned medium fraction (DNTF). Since identification DNTF is ongoing and incomplete, we will also test the relative efficacy of DNTF to promote DA neuron survival and growth as compared to four known growth factors which have demonstrated positive effects on the viability of cultured DA neurons: bFGF, BDNF,IGF-1 and EGF. Both culture and animals studies will collect information on the magnitude of factor induced compensatory changes in the DA system, the relationship to the number and location of DA neurons information on cellular mechanisms of DA neuron growth promotion. Evidence from behavioral measures, immunocytochemical morphology, neurotransmitter and metabolite assays, and measurements of TH mRNA expression will combine to address these issues of interest. In addition, we will pursue our initial finding of enhanced efficacy of embryonic DA neuron grafts in the presence of co-grafted peripheral nerve, by comparing embryonic DA neuron grafts to mixed co-grafts of young and aged rats with short-term (3 weeks) or long-standing (12 months) lesions of the nigrostriatal DA pathway. Further study of Schwann cells and their products as a source of survival and growth- promoting activity for DA neurons may provide insights into the biology of aging as it influences mechanisms of central nervous system plasticity, as well as having exciting implications for experimental therapeutics in aging and Parkinson's disease.