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(申请人提供)：帕金森病是一种常见的神经疾病，其症状主要是由黑质多巴胺神经元丢失和纹状体多巴胺减少引起的。转录因子Nurr1是正常多巴胺神经元发育所必需的，在Nurr1缺失纯合子小鼠的多巴胺神经元不能正常发育的情况下就证明了这一点。Nurr1似乎也在维持正常的多巴胺合成和多巴胺神经元存活方面发挥作用，因为Nurr1基因单一缺失的小鼠在这两个参数上都受到了损害。此外，Nurr1的表达已被证明是由于电活动的变化和治疗后可能影响多巴胺自身受体激活的结果而波动的。这些因素对Nurr1表达的相对贡献尚未确定。基于这一数据，我们假设增加神经元活性和抑制多巴胺自身受体将增加多巴胺神经元中Nurr1的表达。此外，我们假设减弱Nurr1的表达将减弱Nurr1的靶基因、多巴胺的合成和多巴胺神经元的存活。目前，对于成年多巴胺神经元中Nurr1表达的调控机制(S)、Nurr1的变化如何影响多巴胺的合成以及Nurr1如何在多巴胺神经元存活中发挥作用，人们知之甚少。目前建议的具体目的是：1)通过比较单独或与通过反向微透析引入的多巴胺受体激动剂或拮抗剂联合刺激或抑制神经元活性和多巴胺自身受体激活的变化，建立在体内控制Nurr1表达的条件；以及2)通过测量在Nurr1表达减弱的条件下(反义寡核苷酸和Nurr1基因缺失杂合子小鼠的衰老)，确定Nurr1控制多巴胺神经元功能的程度。通过结合激光捕获显微切割技术、实时定量聚合酶链式反应的基因表达技术和基于多重毛细管电泳法的表达谱技术，这些实验将展示这些技术在研究转录因子在神经递质基因调控中的作用，特别是在Nurr1对多巴胺神经递质基因的调控中的作用。长期目标是更好地了解转录因子在多巴胺神经元功能和存活中的作用，因为它们与帕金森病的发病机制有关。目前的提议将确定Nurr1在体内多巴胺神经元中的表达是如何调节的，以及Nurr1如何调节多巴胺的合成和多巴胺神经元的存活。这些数据将有助于确定以Nurr1表达为靶点作为一种手段来提高多巴胺合成和多巴胺神经元存活作为治疗帕金森病的可能性。与公共健康相关，因为帕金森氏症是由制造多巴胺的神经元丧失引起的；目前的治疗方法包括取代多巴胺的药物。然而，这些治疗并不能延缓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防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，既治疗帕金森氏症症状，又/或延缓疾病的进展。