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

基本信息

批准号：
10677221
负责人：
Kwang-Soo Kim
金额：
$ 47.91万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677221
关键词：
1-Methyl-4-phenylpyridinium Address Adopted Affect Alprostadil Amodiaquine Animal Model Behavior Behavioral Biological Assay Brain Brain Diseases Cells 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 Genes Genetic Genetic Transcription Glafenine Health Homologous Gene Immune Impaired cognition Infiltration Inflammatory Laboratories Lewy Bodies Libraries Ligand Binding Domain Ligands Link Maintenance Mediating Microglia Midbrain structure Modeling Molecular Mutation NR4A2 gene Neurodegenerative Disorders Neurotoxins Nuclear Orphan Receptor Nuclear Receptors Olfactory dysfunction Oxidative Stress Induction Parkinson Disease Pathogenesis Pathogenicity Pathologic Patients Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Play Proteins Recovery Regulation Risk Factors Role Structure-Activity Relationship Substantia nigra structure System Testing Transcription Coactivator Transcription Repressor Transcriptional Regulation Translating Work age related aging brain dopaminergic neuron druggable target genetic risk factor high throughput screening improved in vitro Model in vivo Model inhibition of autophagy knock-down motor disorder mutant neuroinflammation neuron development neuron loss neuronal survival neuroprotection novel novel therapeutics overexpression pharmacologic scaffold side effect sporadic Parkinson&apos s Disease symptom treatment synuclein targeted treatment therapeutic development transcription factor

项目摘要

Abstract: Selective degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra and abnormal accumulation and aggregation of -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 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, our preliminary data showed that Nurr1 expression is significantly compromised by both prolonged exposure to neurotoxin and overexpression of -synuclein. Based on these results, we hypothesize that Nurr1 is an “adopted” nuclear receptor whose transcriptional function is significantly modulated by both synthetic and 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 will investigate the underlying molecular mechanisms how these novel ligands regulate Nurr1’s transcriptional function by identifying its coregulators and delineating their structure-activity relationships. Second, we will investigate whether there is crosstalk between Nurr1 and PD risk factors such as -synuclein and how Nurr1’s ligands regulate this crosstalk. Third, using in vivo models of PD, we will systematically investigate whether Nurr1’s optimal 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.

抽象的：黑质中脑多巴胺能 (mDA) 神经元的选择性变性和异常路易体中α-突触核蛋白的积累和聚集是帕金森病的标志性病理特征目前，可用的治疗方法都是针对症状的，没有任何治疗方法可以阻止或减缓这种疾病。基于对 mDA 神经元转录调控的广泛研究。在这个实验室和其他实验室中，孤儿核受体 Nurr1（也称为 NR4A2）已成为大师尽管 Nurr1 一直是 mDA 神经元的调节因子，也是 PD 治疗开发的一个有希望的靶点。被认为是一种不依赖于配体的、组成型活性转录因子，我们鉴定了两种合成的（阿莫地喹、氯喹和格拉芬宁）和内源性配体（前列腺素 E1 (PGE1) 和 PGA1），直接与 Nurr1 的配体结合域 (LBD) 相互作用并以独特的方式激活其转录功能此外，我们的初步数据表明 Nurr1 表达受到显着影响。长期暴露于神经毒素和α-突触核蛋白过度表达基于这些结果，我们。证实 Nurr1 是一种“采用的”核受体，其转录功能受到显着调节由合成配体和天然配体共同作用，并且 Nurr1 和 PD 风险因子之间存在功能串扰。为了解决这些假设，我们建议研究以下问题：首先，我们将解决是否。大脑中存在额外的内源性配体，将研究潜在的分子机制这些新型配体如何通过识别 Nurr1 的辅助调节子并描述其转录功能来调节其转录功能其次，我们将研究 Nurr1 和 Nurr1 之间是否存在串扰。 PD 风险因素，例如 α-突触核蛋白以及 Nurr1 的配体如何调节这种串扰第三，使用体内模型。 PD 的研究中，我们将系统地研究 Nurr1 的最佳合成和/或内源配体是否可以如果成功的话，为最终应用作为PD的新疗法提供基于机制的神经保护。这些研究将加深我们对 Nurr1 的功能及其配体在健康和疾病中的调节的理解。疾病，并解决 Nurr1 是否可以成为 PD 的“可药物”靶点。