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：
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
项目类别：
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

项目摘要

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.

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α-突触核蛋白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，组成型活性转录因子，我们首次确定合成（Amodiaquine，氯喹和格拉非宁）和内源配体（Prostaglandin E1（PGE1）和 PGA1），它直接与Nurr1的配体结合结构域（LBD）相互作用并激活其转录函数具有不同的机制。此外，我们最近发现Nurr1表达受到长期暴露于神经毒素和α-突触核蛋白的过表达。基于这些结果，我们假设Nurr1是一种“采用”的核接收器，可能还有其他原生配体，那里是NURR1和PD风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，我们将解决是否存在其他内源配体大脑以及是否可以产生更好的合成配体，我们将研究这些新型配体如何调节NURR1的转录功能。其次，我们将调查Nurr1之间是否存在串扰和PD危险因素以及Nurr1的配体如何调节该串扰。第三，使用PD体内模型，我们将系统地研究NURR1的合成和/或内源性配体是否可以提供基于机制的最终应用的神经保护作用是PD的新疗法。如果成功，这些研究将进步我们对Nurr1在健康和疾病中的配体的功能和调节的理解，并解决是否是否 Nurr1可以是PD的“可药物”靶标。