TH GENE REGULATION IN HEALTHY AND LESIONED MIDBRAIN

健康和受损中脑中的 TH 基因调控

• 批准号: 6477150
• 负责人: ARNOLD WILLIAM Tank
• 金额: $ 24.69万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477150
• 关键词: 6 hydroxydopamine; AP1 protein; amphetamines; antisense nucleic acid; atropine; cell line; corpus striatum; enzyme induction /repression; experimental brain lesion; glutamate receptor; hexamethonium compound; hormone receptor; laboratory rat; muscarine; neuropeptide receptor; neuropharmacology; substantia nigra; transcription factor; transfection /expression vector; tyrosine 3 monooxygenase

As nigrostriatal neurons degenerate, either during Parkinson's disease or after exposure to neurotoxins, compensatory mechanisms are activated in the surviving striatal nerve terminals to increase dopamine biosynthesis and release. In contrast, gene expression of tyrosine hydroxylase (TH), the enzyme that catalyzes the rate-limiting step in dopamine biosynthesis, is not apparently induced in midbrain cell bodies. This lack of compensatory induction of TH mRNA is surprising, since one would expect robust homeostatic mechanisms to up-regulate TH gene expression and consequently further enhance dopamine biosynthesis in spared nigrostriatal neurons. There is very little information concerning the receptors and intracellular signaling mechanisms that regulate TH gene expression in nigrostriatal neurons. Without this information, it is impossible to understand this lack of compensatory induction and it is difficult to design new therapies to up-regulate TH in surviving nigrostriatal neurons during Early Parkinson's disease or after exposed to neurotoxins. The studies in this proposal are aimed at filling in this gap in our knowledge. The hypotheses being tested in the proposal is that agonists which excite dopaminergic midbrain neurons lead to stimulation of TH gene transcription rate in the midbrain of healthy animals. However, this response may be inhibited in the surviving neurons of animals with lesions of the nigrostriatal pathway. Several aspects of this hypothesis will be tested under the following specific aims: (1) To test whether muscarinic and/or other stimulatory agonists activate whether muscarinic and/or other stimulatory agonists activate TH gene transcription rate and phosphorylate or induce pertinent transcription factors in midbrain cell bodies of healthy rats; (2) To test whether candidate transcription factors are essential for the response of the TH gene to muscarine; and (3) To test whether the TH gene responds to muscarinic (or other stimulatory agonists) in surviving midbrain cell bodies after partial lesions of the nigrostriatal pathway and whether TH gene expression can be induced pharmacologically in these surviving neurons. These studies will shed light on the molecular mechanisms regulating the TH gene in the midbrain and may lead to new therapeutic strategies for the treatment of Parkinson's disease.

当黑质纹状体神经元退化时，无论是在帕金森病期间还是在接触神经毒素后，幸存的纹状体神经末梢的补偿机制被激活，以增加多巴胺的生物合成和释放。相比之下，酪氨酸羟化酶（TH）（催化多巴胺生物合成限速步骤的酶）的基因表达在中脑细胞体中并未明显被诱导。 TH mRNA 代偿性诱导的缺乏是令人惊讶的，因为人们期望强大的稳态机制能够上调 TH 基因表达，从而进一步增强幸存的黑质纹状体神经元中的多巴胺生物合成。 关于调节黑质纹状体神经元 TH 基因表达的受体和细胞内信号传导机制的信息非常少。如果没有这些信息，就不可能理解代偿性诱导的缺乏，并且很难设计新的疗法来上调早期帕金森病期间或暴露于神经毒素后幸存的黑质纹状体神经元中的 TH。本提案中的研究旨在填补我们的知识空白。该提案中测试的假设是，兴奋多巴胺能中脑神经元的激动剂会刺激健康动物中脑中的 TH 基因转录率。然而，在黑质纹状体通路受损的动物的幸存神经元中，这种反应可能受到抑制。该假设的几个方面将在以下具体目标下进行测试：（1）测试毒蕈碱和/或其他刺激性激动剂是否激活健康大鼠中脑细胞体中的毒蕈碱和/或其他刺激性激动剂是否激活TH基因转录率并磷酸化或诱导相关转录因子； (2) 测试候选转录因子是否是TH基因对毒蕈碱反应所必需的； (3)测试黑质纹状体通路部分损伤后幸存的中脑细胞体中TH基因是否对毒蕈碱（或其他刺激性激动剂）有反应，以及在这些幸存的神经元中是否可以通过药理学诱导TH基因表达。这些研究将揭示调节中脑TH基因的分子机制，并可能带来治疗帕金森病的新治疗策略。