Functional Roles of Nurr1 in AD Related Pathophysiology

Nurr1 在 AD 相关病理生理学中的功能作用

• 批准号: 8891618
• 负责人: Kwang-Soo Kim
• 金额: $ 23.7万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891618
• 关键词: Address; Affect; Age; Agonist; Alzheimer' s Disease; Amodiaquine; Amyloid beta-Protein; Animal Model; Animals; Antibodies; Area; Astrocytes; Autopsy; Biochemical; Brain; Cell Count; Cell Death; Cells; Cerebral cortex; Chloroquine; Congresses; Data; Deposition; Development; Disease; Down-Regulation; Exhibits; Functional disorder; Genetic; Genetic screening method; Goals; Hippocampal Formation; Hippocampus (Brain); Immunohistochemistry; Impaired cognition; Inflammation; Injection of therapeutic agent; Ligand Binding Domain; Ligands; Maintenance; Mediator of activation protein; Medical; Microglia; Midbrain structure; Molecular; Mus; Mutation; Neurodegenerative Disorders; Neurons; Nuclear Orphan Receptor; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacological Treatment; Phenotype; Play; Process; Proteins; Reporting; Research; Role; Societies; Staging; Strategic Planning; Structure; Subfamily lentivirinae; Synapses; Testing; Time; Transcription Factor 3; Transgenic Mice; Wild Type Mouse; age related; aging population; base; behavior test; behavioral outcome; burden of illness; cognitive function; conditioned fear; dopaminergic neuron; familial Alzheimer disease; frontal lobe; gain of function; genetic approach; loss of function; mind control; neuroinflammation; neuron loss; neuronal survival; neurotoxic; novel; novel therapeutic intervention; object recognition; overexpression; public health relevance; small hairpin RNA; small molecule; social; therapeutic development; transcription factor

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common neurodegenerative disease, affects more than 35 million patients worldwide (>5 million in US). With an aging population, the number of people suffering from AD and the burden on our society will escalate; a recent report by the US Congress estimates that federal spending on AD will increase to over $1 trillion (in today's dollars) per year by 2050 (A National Alzheimer's Strategic Plan: The report of the Alzheimer's study group, 2009; ://www.alz.org/documents/national/report_asg_alzplan.pdf). Since there is no therapy that can slow down or halt the disease process, it is of paramount significance to identify novel pathways and mediators that critically regulate the pathophysiology of AD. The orphan nuclear receptor Nurr1 play a critical role for development and maintenance of midbrain dopamine neurons as well as their protection from inflammation-induced cell death. However, its role in Alzheimer's disease (AD)-related pathogenesis is completely unknown. Although Nurr1 is considered to be a ligand-independent and constitutively active transcription factor, we recently identified small molecules (e.g., amodiaquine (AQ) and chloroquine (CQ)) that prominently modulate Nurr1's transcriptional function via direct interaction with its ligand-binding domain (LBD), suggesting that Nurr1's activity can be modulated by agonists/synthetic ligands. Furthermore, using our Nurr1-specific antibodies, we found that Nurr1 is prominently expressed in the hippocampal formation and frontal cortex and that the number of Nurr1-expressing cells significantly declines in the 5XFAD mouse, a valid animal model of AD, in an age-dependent manner, accompanied with increased plaque deposition. In addition, we found that Nurr1 expression is significantly reduced in the hippocampus of AD postmortem brain, compared with age-matched healthy control brain, suggesting that Nurr1 may have functional roles related to AD pathophysiology. Based on these findings, this proposal will address our hypothesis that Nurr1 plays critical roles in AD-related pathophysiology and that Nurr1 activation by its agonist(s) provides a novel therapeutic approach for AD. If goals of this project are successfully achieved, it will spark a new direction of AD research by demonstrating that Nurr1 is a key mediator and a valid target for therapeutic development.

 描述（由申请人提供）：阿尔茨海默病 (AD) 是最常见的神经退行性疾病，影响全球超过 3500 万患者（美国超过 500 万）。随着人口老龄化，AD的患病人数和社会负担将会增加；美国国会最近的一份报告估计，到 2050 年，联邦政府在 AD 方面的支出将增加到每年 1 万亿美元以上（以今天的美元计算）（国家阿尔茨海默病战略计划：阿尔茨海默病研究小组的报告，2009 年；://www.alz.org/documents/national/report_asg_alzplan.pdf）。由于没有任何疗法可以减缓或停止疾病过程，因此识别关键调节 AD 病理生理学的新途径和介质至关重要。孤儿核受体 Nurr1 对于中脑多巴胺神经元的发育和维持以及保护它们免受炎症诱导的细胞死亡起着至关重要的作用。然而，其在阿尔茨海默病（AD）相关发病机制中的作用尚不清楚。尽管 Nurr1 被认为是一种不依赖配体且具有组成型活性的转录因子，但我们最近发现了一些小分子（例如阿莫地喹 (AQ) 和氯喹 (CQ)），它们通过与其配体结合域 (LBD) 直接相互作用来显着调节 Nurr1 的转录功能，这表明 Nurr1 的活性可以通过激动剂/合成物来调节 配体。此外，使用我们的 Nurr1 特异性抗体，我们发现 Nurr1 在海马结构和额叶皮层中显着表达，并且在 5XFAD 小鼠（一种有效的 AD 动物模型）中，表达 Nurr1 的细胞数量以年龄依赖性方式显着下降，并伴有斑块沉积增加。此外，我们发现与年龄匹配的健康对照大脑相比，AD死后大脑海马中Nurr1的表达显着降低，这表明Nurr1可能具有与AD病理生理学相关的功能作用。基于这些发现，本提案将解决我们的假设，即 Nurr1 在 AD 相关病理生理学中发挥关键作用，并且 Nurr1 的激动剂激活为 AD 提供了一种新的治疗方法。如果该项目的目标成功实现，它将证明 Nurr1 是治疗开发的关键介质和有效靶标，从而激发 AD 研究的新方向。