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

NURR1 在调节神经毒素引起的多巴胺神经元损伤中的作用

• 批准号: 7381818
• 负责人: JEFFREY B EELLS
• 金额: $ 4.83万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381818
• 关键词: ROLE; NURR1; REGULATION; DOPAMINE; NEURON

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.

该主题是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是针对该中心的，这不是调查人员的机构。帕金森氏病（PD）是一种进行性的神经退行性疾病，主要是由于黑质中多巴胺神经元的丧失以及随后在纹状体中多巴胺的损失引起的。疾病的原因尚不清楚。但是，被认为有助于PD的最突出的变量是衰老，暴露于各种环境毒素（尤其是农药）和遗传因素。转录因子NURR1对于中脑多巴胺神经元的分化至关重要，但对于成熟的多巴胺神经元的存活似乎也很重要。目前，问题在于，NurR1在多巴胺神经元的存活以及这种影响毒素和农药诱导神经变性的机制中知之甚少。当前项目的目的是1）通过使用反义来确定Nurr1在多巴胺神经元中的作用，以敲低Nurr1在多巴胺神经元中的表达和2）2）比较多巴胺神经元在Nurr1-Nurr 1-无杂合小鼠中的多巴胺神经元的差异易感性与野生型小鼠与野生型Intirect contectic and para andecth and lip rip rip contrecha and cortense and cortense and cortense and cortense and cortense and cortense and cortense and cortense and cortense and cortense and cortense and cortense and。我们假设在NURR1无杂合小鼠或反义治疗后发现的Nurr1表达会使多巴胺神经元更容易受到毒素和农药的易感性，这些神经元更容易受到毒素和农药的影响，这些神经元特别损害了多巴胺神经元，并且通过评估这种确定的多巴胺神经变性性的进展，可以评估多巴胺神经变性的进展。这项研究的基本原理是，一旦了解了Nurr1。在多巴胺神经元中的功能作用，请更好地欣赏帕金森氏病的发病机理，并且无疑将随后进行治疗。