Regulation and function of Nurr1 in adult nigrostriatal dopamine neurons

Nurr1 在成人黑质纹状体多巴胺神经元中的调节和功能

• 批准号: 7588430
• 负责人: JEFFREY B EELLS
• 金额: $ 15.29万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588430
• 关键词: Adult; Affect; Aftercare; Age; Aging; Antisense Oligonucleotides; Attenuated; Autoreceptors; Capillary Electrophoresis; Chronic; Cocaine; Condition; Corpus striatum structure; Data; Development; Disease; Disease Progression; Disruption; Dopamine; Dopamine Agonists; Dopamine D2 Receptor; Drug usage; Enzymes; Equipment; Essential Genes; Failure; Future; GTP Cyclohydrolase I; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Goals; In Vitro; Individual; Injection of therapeutic agent; Investigation; Link; Measures; Microdialysis; Midbrain structure; Mississippi; Mus; Neurodegenerative Disorders; Neurons; Numbers; Parkinson Disease; Pathogenesis; Personal Satisfaction; Pharmaceutical Preparations; Phenotype; Phenylalanine; Polymerase Chain Reaction; Population; Prevalence; Principal Investigator; Production; Public Health; RNA Splicing; Rate; Regulation; Relative (related person); Research; Role; Stem cells; Substantia nigra structure; Symptoms; Techniques; Technology; Testing; Time; Toxic Environmental Substances; Transcription factor genes; Tyrosine 3-Monooxygenase; United States; Universities; Variant; Work; base; cofactor; dopaminergic neuron; expectation; extracellular; in vivo; innovation; laser capture microdissection; nervous system disorder; neuron loss; neurotransmission; novel; research study; tetrahydrobiopterin; transcription factor

DESCRIPTION (provided by applicant): Parkinson's disease is a common neurological disorder, the symptoms of which are caused primarily by a loss of dopamine neurons in the substantia nigra and reduced dopamine in the striatum. The transcription factor Nurr1 is necessary for normal dopamine neuron development as demonstrated by a failure of dopamine neurons to develop properly in Nurr1-null homozygous mice. Nurr1 also appears to function in maintaining normal dopamine synthesis and dopamine neuron survival as mice with a single deletion of the Nurr1 gene are impaired in both parameters. Additionally, the expression of Nurr1 has been shown to fluctuate as a result of changes in electrical activity and after treatments that can affect the activation of dopamine autoreceptors. The relative contribution of these factors on Nurr1 expression have not been determined. Based on this data, we hypothesize that increasing neuronal activity and inhibition of dopamine autoreceptors will increase Nurr1 expression in dopamine neurons. Furthermore, we hypothesize that attenuating Nurr1 expression will attenuate target genes of Nurr1, dopamine synthesis and dopamine neuron survival. Currently, little is known about the mechanism(s) that regulate Nurr1 expression in adult dopamine neurons, how changes in Nurr1 affect dopamine synthesis or how Nurr1 functions in dopamine neuron survival. The specific aims of the current proposal are 1) to establish the conditions that control Nurr1 expression in dopamine neurons in vivo by comparing the contributions of changes in neuronal activity and dopamine autoreceptor activation by stimulating or inhibiting activity alone or in combination with a dopamine receptor agonist or antagonist introduced via reverse microdialysis, and 2) to identify the extent by which Nurr1 controls dopamine neuron function by measuring changes in dopamine neuron gene expression and parameters of dopamine synthesis and changes in dopamine neuron survival in conditions of attenuated Nurr1 expression (antisense oligonucleotides and aging in Nurr1-null heterozygous mice). By using a combination of laser capture microdissection with gene expression technology of quantitative real-time PCR and eXpress profiling multiplex capillary electrophoresis based quantitative PCR; these experiments will demonstrate the utility of these techniques for investigating the role of transcription factors in the regulation of neurotransmission genes and specifically, the regulation of dopamine neurotransmission genes by Nurr1. The long term goal is to better understand the role of transcription factors in the function and survival of dopamine neurons as they relate to the pathogenesis of Parkinson's disease. The current proposal will ascertain how Nurr1 expression in dopamine neurons is regulated in vivo and how Nurr1 functions to regulate dopamine synthesis and survival of dopamine neurons. This data will aid in determining the potential for targeting Nurr1 expression as a means to elevate dopamine synthesis and dopamine neuron survival as a treatment of Parkinson's disease. PUBLIC HEALTH RELEVANCE Since Parkinson's disease is caused by a loss of neurons that make dopamine; the current treatments consist of drugs that replace dopamine. These treatments, however, do not delay the loss of dopamine neurons or the progression of the disease. By understanding how specific genes control the production of dopamine and keep dopamine neurons from dying, new treatments targeting the expression of these genes can be developed that both treat Parkinson's disease symptoms and/or delay the progression of this disease.

描述（由申请人提供）：帕金森氏病是一种常见的神经系统疾病，其症状主要是由棘质尼格拉（Nigra）中多巴胺神经元的丧失引起的，并减少了纹状体中的多巴胺。转录因子Nurr1对于正常多巴胺神经元发育是必需的，这是多巴胺神经元失败在Nurr1无纯合小鼠中正确发育的。 Nurr1在维持正常多巴胺合成和多巴胺神经元存活中似乎还起作用，因为在两个参数中都损害了Nurr1基因的单个缺失的小鼠。另外，由于电活动的变化以及可能影响多巴胺自身受体激活的处理后，Nurr1的表达已被证明会波动。这些因素对NURR1表达的相对贡献尚未确定。基于这些数据，我们假设增加神经元活性和抑制多巴胺自身受体会增加多巴胺神经元中的NurR1表达。此外，我们假设衰减NURR1表达将减轻NURR1，多巴胺合成和多巴胺神经元存活的靶基因。当前，对调节成年多巴胺神经元中Nurr1表达的机制知之甚少，Nurr1的变化如何影响多巴胺合成或Nurr1在多巴胺神经元中的作用。当前建议的具体目的是1）建立通过比较神经元活性和多巴胺自身受体自身受体的变化来控制体内多巴胺神经元表达的条件，通过单独或通过抑制多巴胺受体受体或拮抗剂的范围以及反向微磷的范围和2）来刺激或抑制活性来激活的贡献。多巴胺神经元通过测量多巴胺神经元基因表达的变化和多巴胺合成的参数以及在衰减Nurr1表达的条件下多巴胺神经元的生存的变化（反义寡核苷酸和Nurr1-无核苷酸中的反义寡核苷酸和衰老的衰老）。通过使用激光捕获显微解剖与定量实时PCR的基因表达技术和基于定量毛细管电泳的基因表达技术；这些实验将证明这些技术在调节神经传递基因调节中的作用，特别是调节多巴胺神经传递基因Nurr1的作用。长期目标是更好地了解转录因子在与帕金森氏病的发病机理相关的多巴胺神经元功能和存活中的作用。当前的建议将确定多巴胺神经元中的NURR1表达如何在体内调节，以及Nurr1如何调节多巴胺神经元的多巴胺合成和存活率。该数据将有助于确定靶向NURR1表达的潜力，以此作为提升多巴胺合成和多巴胺神经元存活的一种手段，作为对帕金森氏病的治疗方法。公共卫生相关性，因为帕金森氏病是由多巴胺造成的神经元丧失引起的；当前的治疗方法由替代多巴胺的药物组成。但是，这些治疗方法不会延迟多巴胺神经元的丧失或疾病的进展。通过了解特定基因如何控制多巴胺的产生并阻止多巴胺神经元死亡，可以开发针对这些基因表达的新疗法，以治疗帕金森氏病症状和/或延迟这种疾病的进展。