NEUREGULINS AND NIGROSTRIATAL SYSTEM FUNCTION

描述（来自申请人的摘要）：帕金森病是 以黑质纹状体多巴胺能神经元的进行性变性为特征， 中脑腹侧的神经元虽然基本的潜在机制， 这种使人衰弱的运动障碍仍然是未知的，相当大的努力， 以制定有效的策略来阻止神经退行性疾病为中心 并恢复正常功能。一种有希望的方法是使用 神经营养因子，蛋白质，促进生存和适当的 选择神经元群体的功能。我们的初步调查结果 实验室显示，一组相对较新 称为神经调节素的营养因子在多巴胺能神经元内合成。 啮齿动物和灵长类动物的黑质纹状体系统。我们发现， 神经调节素的施用诱导增加的多巴胺溢出， 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还表明，神经调节蛋白治疗可以保护 多巴胺能细胞对抗体内神经毒素诱导的变性， 体外氧化和代谢损伤。在这项研究中，我们 我将在这些发现的基础上进行扩展，以检验总体假设， 神经调节蛋白对中脑具有神经保护和/或神经恢复作用 多巴胺能神经元的选择性神经毒性损伤。具体目标#1 确定神经调节蛋白受体表达的程度， 多巴胺能细胞在腹侧中脑正常和 神经毒素损伤大鼠和猴的原位单标记和双标记 杂交和免疫细胞化学技术。具体目标#2将使用 帕金森病的良好表征的大鼠模型加上特定的 neuregulin治疗方案，以测试输注neuregulin（I）是否保护 多巴胺能神经元免受随后的神经毒性损伤，或（ii）促进 神经毒性后受损黑质纹状体系统的功能恢复 损害形态学、行为学和神经化学方法将用于 分析保护和/或功能恢复的程度， neuregulin治疗具体目标#3将（I）确定神经调节蛋白受体 表达在大鼠和猴中是空间或时间缺陷的 老年动物的黑质纹状体系统，和（ii）使用脑内 微透析，评估多巴胺能黑质纹状体的反应性 系统对年轻、中年和老年大鼠施用神经调节蛋白的影响。具体 目的#4将评估neuregulin保护的潜在机制 多巴胺能细胞免受帕金森氏病相关损伤。总的来说，这些 研究将评估神经调节蛋白营养因子对 帕金森氏病和其他神经变性疾病的治疗 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.