Crosstalk between Nurr1 and risk factors of Parkinson's disease and its regulation by Nurr1's ligands

Nurr1与帕金森病危险因素的串扰及其配体的调控

• 批准号: 10592731
• 负责人: Kwang-Soo Kim
• 金额: $ 52.55万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592731
• 关键词: 1-Methyl-4-phenylpyridinium; Address; Adopted; Affect; Alprostadil; Amodiaquine; Animal Model; Behavioral; Binding; Biological Assay; Brain; Cessation of life; Chloroquine; Complex; Data; Dependovirus; Development; Disease; Disease Progression; Down-Regulation; Drug Targeting; Dyskinetic syndrome; Effectiveness; Environmental Risk Factor; Exposure to; FDA approved; Future; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Transcription; Glafenine; Health; Homologous Gene; Impaired cognition; Inflammatory; Knowledge; Laboratories; Lewy Bodies; Ligand Binding; Ligand Binding Domain; Ligands; Link; Maintenance; Mediating; Microglia; Midbrain structure; Modeling; Molecular; Mutation; NR4A2 gene; Neurodegenerative Disorders; Neurons; Neurotoxins; Nuclear Orphan Receptor; Nuclear Receptors; Olfactory dysfunction; Orphan; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmacology; Physiological; Play; Proteins; Recovery; Regulation; Risk Factors; Role; Rotenone; Substantia nigra structure; System; Testing; Time; Transcription Coactivator; Transcription Repressor; Transcriptional Regulation; Translating; Work; aging brain; base; dopaminergic neuron; druggable target; high throughput screening; improved; in vitro Model; in vivo Model; motor disorder; mouse model; mutant; neuroinflammation; neuron loss; neuroprotection; novel; novel therapeutics; overexpression; quinoline; receptor; scaffold; side effect; small molecule libraries; symptom treatment; synuclein; targeted treatment; therapeutic development; transcription factor

Abstract: Selective degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra and abnormal accumulation and aggregation of α-synuclein in Lewy bodies are hallmark pathological features of Parkinson’s disease (PD). Currently, available treatments are symptomatic and there is no treatment that can halt or slow down the disease progression. Based on extensive studies on transcriptional regulation of mDA neurons from this and other laboratories, the orphan nuclear receptor Nurr1 (also known as NR4A2) has emerged as a master regulator of mDA neurons and a promising target for therapeutic development in PD. Although Nurr1 has been considered a ligand-independent, constitutively active transcription factor, we for the first time identified both synthetic (amodiaquine, chloroquine, and glafenine) and endogenous ligands (prostaglandin E1 (PGE1) and PGA1), which directly interact with the ligand binding domain (LBD) of Nurr1 and activate its transcription function with distinct mechanisms. Furthermore, we recently found that Nurr1 expression is significantly compromised by both prolonged exposure to neurotoxin and overexpression of α-synuclein. Based on these results, we hypothesize that Nurr1 is an “adopted” nuclear receptor and may have additional native ligands and that there is functional crosstalk between Nurr1 and PD risk factors. To address these hypotheses, we propose to investigate the following questions. First, we will address whether there exist additional endogenous ligands in the brain and whether better synthetic ligands can be generated, and we will investigate how these novel ligands regulate Nurr1’s transcriptional function. Second, we will investigate whether there is crosstalk between Nurr1 and PD risk factors and how Nurr1’s ligands regulate this crosstalk. Third, using in vivo models of PD, we will systematically investigate whether Nurr1’s synthetic and/or endogenous ligands can provide mechanism-based neuroprotection for eventual application as novel therapeutics for PD. If successful, these studies will advance our understanding of Nurr1’s function and regulation by its ligands in health and disease, and address whether Nurr1 can be a “druggable” target for PD.

摘要： 黑质中脑多巴胺能神经元选择性变性及异常 α-突触核蛋白在路易小体的聚集和聚集是帕金森病的显著病理特征 疾病(PD)。目前，可用的治疗是有症状的，没有可以停止或减缓的治疗。 延缓疾病的发展。基于对丙二醛神经元转录调控的广泛研究 这个实验室和其他实验室一样，孤儿核受体Nurr1(也被称为NR4A2)已经成为大师 丙二醛神经元的调节剂，是帕金森病治疗发展的一个有前途的靶点。尽管Nurr1已经 被认为是一种不依赖配体的、构成活性的转录因子，我们首次鉴定了这两种转录因子 合成的(阿莫地喹、氯喹和格拉芬)和内源性配体(前列腺素E_1(PGE_1)和 PGA1)，直接与Nurr1的配体结合域(LBD)相互作用，激活其转录功能 有着不同的机制。此外，我们最近发现，Nurr1的表达受到 神经毒素暴露时间延长，α-突触核蛋白过度表达。基于这些结果，我们 假设Nurr1是一种“被收养的”核受体，可能有额外的天然配体，并且 Nurr1和帕金森病危险因素之间的功能串扰。为了解决这些假设，我们建议 调查以下问题。首先，我们将讨论是否存在额外的内源性配体 以及是否可以产生更好的合成配体，我们将研究这些新的配体是如何 调节Nurr1‘S转录功能。其次，我们将调查Nurr1之间是否存在串扰 和PD风险因素，以及Nurr1‘S配体如何调节这种串扰。第三，使用帕金森病的活体模型，我们将 系统研究Nurr1‘S合成和/或内源性配体是否能提供基于机制的 最终作为帕金森病新疗法应用的神经保护。如果成功，这些研究将会取得进展 我们对Nurr1‘S的功能及其配体在健康和疾病中的调节的理解，并解决了 Nurr1可作为帕金森病的“可用药”靶点。