ROLE OF NURR1 IN THE REGULATION OF DOPAMINE NEURON DAMAGE INDUCED BY NEUROTOXINS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。帕金森帕金森氏病（PD）是一种进行性神经退行性疾病，主要由黑质中多巴胺神经元的损失和随后纹状体中多巴胺的损失引起。疾病的原因尚不清楚;然而，被认为导致PD的最突出的变量是衰老，暴露于各种环境毒素（特别是农药）和遗传因素。转录因子Nurr 1对于中脑多巴胺神经元的分化是必不可少的，但似乎对于成熟多巴胺神经元的存活也很重要。目前，问题是关于Nurr 1在多巴胺神经元存活中发挥作用的机制以及这如何影响毒素和农药诱导的神经变性知之甚少。本项目的目的是：1）通过使用反义基因敲低多巴胺神经元中的Nurr 1表达来确定Nurr 1在多巴胺神经元存活中的作用; 2）比较Nurr 1缺失杂合子小鼠与野生型小鼠中多巴胺神经元对百草枯、鱼藤酮和脂多糖注射液的神经毒性损伤的不同易感性。我们假设，减弱Nurr 1表达，如发现在Nurr 1无效杂合子小鼠或反义治疗后，将使多巴胺神经元更容易受到毒素和农药，专门损害多巴胺神经元，并通过评估多巴胺神经变性的进展，这种增加的易感性的原因可以确定。这项研究的基本原理是，一旦了解了Nurr 1在多巴胺神经元中的功能作用，无疑将更好地了解帕金森病的发病机制及其治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Parkinson¿s disease (PD) is a progressive, neurodegenerative disorder caused primarily by the loss of dopamine neurons in the substantia nigra and the subsequent loss of dopamine in the striatum. The cause of the disease is unclear; however, the most prominent variables that are thought to contribute to PD are aging, exposure to various environmental toxins (especially pesticides) and genetic factors. The transcription factor Nurr1 is essential for the differentiation of midbrain dopamine neurons, but is also appears to be important for survival of mature dopamine neurons. Currently, the problem is that little is known about the mechanism(s) through which Nurr1 functions in survival of dopamine neurons and how this effects toxin and pesticide induced neurodegeneration. The objective of the current project is to 1) determine the role of Nurr1 in dopamine neuron survival by using antisense to knockdown Nurr1 expression in dopamine neurons and 2) compare differential susceptibility of dopamine neurons in Nurr1-null heterozygous mice with wild-type mice to neurotoxic insults of paraquat, rotenone and lipopolysaccharide injection. We hypothesize that attenuated Nurr1 expression, as found in the Nurr1-null heterozygous mice or after antisense treatment, will make dopamine neurons more susceptible to toxins and pesticides that specifically damage dopamine neurons and, by evaluating the progression of dopamine neurodegeneration, the cause of this increased susceptibility can be determined. The rationale for this study is that once Nurr1¿s functional role in dopamine neurons is understood, better appreciation of the pathogenesis of Parkinson¿s disease and its treatment will undoubtedly follow.