NEUREGULINS AND NIGROSTRIATAL SYSTEM FUNCTION

神经调节蛋白和黑质纹状体系统功能

• 批准号: 6451316
• 负责人: KIM B SEROOGY
• 金额: $ 5万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-10 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6451316
• 关键词: PC12 cells; Parkinson's disease; Primates; aging; dopamine; growth factor receptors; in situ hybridization; laboratory rat; microdialysis; nervous system regeneration; neuroprotectants; neurotoxins; neurotrophic factors; oxidative stress; receptor expression; substantia nigra; western blottings

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.

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进行性退化为特征 中脑腹侧的神经元。虽然基本的底层机制 这种使人衰弱的运动障碍仍然未知，但人们已付出巨大努力 重点是制定有效的策略来阻止神经退行性疾病 过程并恢复正常功能。一种有前途的方法涉及使用 神经营养因子、促进生存的蛋白质和适当的 选定的神经元群体的功能。我们的初步调查结果 实验室表明，一组相对新颖的受体 mRNA 和蛋白质 称为神经调节蛋白的营养因子是在多巴胺能细胞内合成的 啮齿类动物和灵长类动物的黑质纹状体系统。我们发现黑上 给予神经调节蛋白会导致多巴胺溢出增加 纹状体，表明对多巴胺能黑质纹状体的功能影响 系统。我们最近的数据还表明，神经调节蛋白治疗可以保护 多巴胺能细胞对抗神经毒素诱导的体内变性，并对抗 体外氧化和代谢损伤。在拟议的研究中，我们 将扩展这些发现来检验总体假设 神经调节蛋白对中脑具有神经保护和/或神经恢复作用 选择性神经毒性损伤后的多巴胺能神经元。具体目标#1 将 确定神经调节蛋白受体表达的程度 正常和正常人腹侧中脑的多巴胺能细胞 使用原位单标记和双标记对神经毒素损伤的大鼠和猴子进行研究 杂交和免疫细胞化学技术。具体目标 #2 将使用 特征明确的帕金森病大鼠模型加上特定的 神经调节蛋白治疗方案以测试输注神经调节蛋白 (I) 是否具有保护作用 多巴胺能神经元免受随后的神经毒性损伤或（ii）促进 神经中毒后受损黑质纹状体系统的功能恢复 损害。将使用形态学、行为学和神经化学方法 分析所提供的保护和/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是否 大鼠和猴子中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、中年和老年大鼠进行神经调节蛋白给药。具体的 目标#4将评估神经调节蛋白保护的潜在机制 来自与帕金森病相关的损伤的多巴胺能细胞。总体而言，这些 研究将评估神经调节蛋白营养因子的治疗价值 帕金森病和其他神经退行性疾病的治疗 黑质纹状体系统。