NEUREGULINS AND NIGROSTRIATAL SYSTEM FUNCTION

描述(摘自申请者的摘要)：帕金森氏症 以黑质纹状体多巴胺能神经元进行性变性为特征 腹侧中脑的神经元。尽管基本的底层机制 这种衰弱的运动障碍仍然未知，已经做出了相当大的努力 中心是开发有效的策略来阻止神经退行性变 处理并恢复正常功能。一种有希望的方法涉及到使用 神经营养因子，促进生存和适当的蛋白质 精选的神经元群体的功能。来自我们的初步调查结果 实验室研究表明，受体的信使核糖核酸和蛋白质为一组相对新颖的 被称为神经调节蛋白的营养因子在多巴胺能神经元中合成 啮齿动物和灵长类动物的黑质纹状体系统。我们发现在黑质上 应用神经调节素可诱导大鼠脑内多巴胺溢出增加 纹状体，表明对多巴胺能黑质纹状体的功能影响 系统。我们最近的数据也表明，中性调节蛋白治疗可以保护 多巴胺能细胞在体内对抗神经毒素诱导的变性，并对抗 在体外氧化和新陈代谢的侮辱。在拟议的研究中，我们 将在这些发现的基础上进行扩展，以检验总体上的假设 神经调节素对中脑具有神经保护和/或神经修复作用 选择性神经毒性损伤下的多巴胺能神经元。具体目标#1将 确定神经调节蛋白受体的表达程度 正常和正常大鼠中脑腹侧的多巴胺能细胞 神经毒素损伤大鼠和猴的单、双标记原位研究 杂交和免疫细胞化学技术。特定目标#2将使用 特征明确的帕金森病大鼠模型与特异性 中性调节蛋白治疗方案测试输注中性调节蛋白(I)是否具有保护作用 多巴胺能神经元免受后续神经毒性损伤或(Ii)促进 神经中毒后受损黑质纹状体系统的功能恢复 损坏。将使用形态、行为和神经化学方法来 分析由提供的保护和/或功能恢复的程度 神经调节蛋白治疗。具体目标#3将(I)确定神经调节蛋白受体 大鼠和猴子的表达在空间或时间上存在缺陷 老年动物的黑质纹状体系统，以及(Ii)使用脑内 微透析，评价黑质纹状体多巴胺能神经元的反应性 幼年、中年和老年大鼠神经调节蛋白给药系统。特定的 目标#4将评估神经调节蛋白保护的潜在机制 与帕金森氏症相关的侮辱产生的多巴胺能细胞。总的来说，这些 研究将评估中性调节蛋白营养因子对 帕金森病和其他神经退行性疾病的治疗 黑质纹状体系统。

DESCRIPTION (From the applicant's abstract): Parkinson's disease is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons in the ventral midbrain. Although the basic underlying mechanisms of this debilitating movement disorder remain unknown, considerable efforts have centered on developing effective strategies for halting the neurodegenerative process and restoring normal function. One promising approach involves the use of neurotrophic factors, proteins that promote the survival and proper functioning of select populations of neurons. Preliminary findings from our laboratory show that receptor mRNA and protein for a relatively novel group of trophic factors called neuregulins are synthesized within the dopaminergic nigrostriatal system in rodents and primates. We find that supranigral administration of neuregulin induces increased dopamine overflow in the striatum, indicating functional effects upon the dopaminergic nigrostriatal system. Our recent data also indicate that neuregulin treatment protects dopaminergic cells against neurotoxin-induced degeneration in vivo, and against both oxidative and metabolic insults in vitro. In the proposed research, we will expand upon these findings to test the overall the hypothesis that neuregulins are neuroprotective and/ or neurorestorative for midbrain dopaminergic neurons upon selective neurotoxic damage. Specific Aim #1 will determine the extent to which neuregulin receptors are expressed by dopaminergic cells in the ventral mesencephalon of normal and neurotoxin-lesioned rat and monkey using single- and double-labeling in situ hybridization and immunocytochemical techniques. Specific Aim #2 will use a well-characterized rat model of Parkinson's disease coupled with specific neuregulin treatment regims to test if infusion of neuregulins (I) protects dopaminergic neurons from subsequent neurotoxic damage or (ii) promotes functional recovery of the injured nigrostriatal system after neurotoxic damage. Morphological, behavioral and neurochemical approaches will be used to analyze the extent of protection and/or functional restoration afforded by neuregulin treatment. Specific aim #3 will (I) determine if neuregulin receptor expression is spatially or temporally deficient in the rat and monkey nigrostriatal system in aged animals, and (ii) using intracerebral microdialysis, evaluate the responsiveness of the dopaminergic nigrostriatal system to neuregulin administration in young, middle age and old rats. Specific aim #4 will assess the potential mechanisms by which neuregulin protects dopaminergic cells from insults relevent to Parkinson's disease. Overall, these studies will assess the therapeutic value of neuregulin trophic factors for the treatment of Parkinson's disease and other neurodegenerative disorders of the nigrostriatal system.