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：黑质和异常中脑多巴胺能（MDA）神经元的选择性变性路易尸体中核素的积累和聚集是帕金森氏症的标志性病理特征疾病（PD）。目前，可用治疗是有症状的，没有可以停止或缓慢的治疗方法降低疾病的进展。基于对MDA神经元转录调控的广泛研究这个和其他实验室，孤儿核接收器Nurr1（也称为NR4A2）已成为主人尽管Nurr1一直是MDA神经元的调节剂，也是PD治疗发展的有希望的靶标。被认为是不依赖配体的，始终如一的活性转录因子，我们确定了这两个合成（Amodiaquine，氯喹和llafenine）和内源配体（Prostaglandin E1（PGE1）和PGA1），它们直接与Nurr1的配体结合域（LBD）直接相互作用，并以不同的方式激活其转录函数机制。此外，我们的初步数据表明，Nurr1表达显着损害了长时间暴露于神经毒素和核蛋白的过表达。基于这些结果，我们假设Nurr1是一个“采用”的核接收器，其转录功能受到显着调节通过合成和天然配体，Nurr1和PD风险因素之间存在功能性串扰。到解决这些假设，我们建议调查以下问题。首先，我们将解决是否大脑中还有其他内源配体，并将研究潜在的分子机制这些新颖的配体如何通过识别其核心调节剂并描绘Nurr1的转录功能来调节Nurr1的转录功能他们的结构活动关系。其次，我们将调查Nurr1和 PD危险因素，例如核蛋白以及Nurr1的配体如何调节该串扰。第三，使用体内模型在PD中，我们将系统地研究Nurr1的最佳合成和/或内源性配体是否可以提供基于机制的神经保护作用，以最终作为PD的新疗法。如果成功，这些研究将促进我们对Nurr1在健康方面的功能和调节的理解，疾病，并解决NURR1是否可以成为PD的“可药”靶标。