Molecular basis of activation of the orphan nuclear receptor Nurr1

孤儿核受体 Nurr1 激活的分子基础

基本信息

批准号：
10831795
负责人：
Douglas Kojetin
金额：
$ 56.96万
依托单位：
VANDERBILT UNIVERSITY
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：
2023-04-25 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10831795
关键词：
Adjuvant Affect Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Animal Model Binding Biochemical Biological Assay Brain Cell model Cells Cellular Assay Chemicals Complex Coupled Data Dementia Deuterium Development Disease Dissociation Docosahexaenoic Acids Drug Targeting Endocannabinoids Excretory function Genetic Transcription Goals Heterodimerization Homeostasis Hydrogen Knowledge Ligand Binding Ligand Binding Domain Ligands Maintenance Mass Spectrum Analysis Molecular Molecular Conformation Movement NMR Spectroscopy NR4A2 gene Nerve Degeneration Neurons Nuclear Orphan Receptor Nuclear Receptors Outcome PPAR gamma Parkinson Disease Pathogenesis Pharmaceutical Preparations Publishing RXR Regulation Reporting Repression Roentgen Rays Specificity Structure Surface Therapeutic Therapeutic Agents Thyroid Hormones Tissues Unsaturated Fatty Acids Work X-Ray Crystallography abeta accumulation age related neurodegeneration antagonist brain tissue crosslink design dopaminergic neuron improved monomer multidisciplinary neuroinflammation neuron loss neuroprotection new therapeutic target novel permissiveness rational design small molecule structural biology transcription factor

项目摘要

Small molecule ligands that activate the orphan nuclear receptor Nurr1 (NR4A2) hold promise as neuroprotective therapeutic agents or adjuvants to aging-associated neurodegenerative and dementia disorders characterized by a loss of neuron function including Parkinson's disease (PD) and Alzheimer's disease (AD). Nurr1 activating ligands show functional efficacy in animal models of AD and PD. However, although nuclear receptors are considered to be ligand-dependent transcription factors, Nurr1 is thought to function independent of binding an endogenous ligand that is produced and present in cells. Several synthetic ligands that activate Nurr1 transcription have been reported, but most have not been validated to directly bind Nurr1 and their mechanism of action remains unknown, which has stunted efforts to optimize Nurr1 ligands for AD and PD. Furthermore, Nurr1 regulates transcription as a monomer and as a Nurr1-RXR heterodimer. Synthetic RXR ligands that activate transcription of Nurr1-RXR heterodimers also display functional efficacy in animal models of AD and PD. However, it remains poorly understood how RXR and RXR-binding ligands impact the function of Nurr1-RXR on the structural level. In this project, we will address these knowledge gaps using mechanistic studies to deﬁne how small molecule ligands impact Nurr1 and Nurr1-RXR activation on the molecular, structural, and cellular levels using NMR spectroscopy, X-ray crystallography, mass spectrometry coupled to hydrogen/deuterium exchange (HDX-MS) and chemical crosslinking (XL-MS) and small angle X-ray scattering along with biochemical and cellular functional assays. These data will inform the design of new and improved Nurr1 activating ligands to determine if direct targeting of Nurr1 or indirect targeting via RXR is a viable option for AD and PD treatment

激活孤儿核受体NURR1（NR4A2）的小分子配体作为神经保护治疗剂或对衰老相关的神经变性和痴呆症的调节剂的承诺是有希望的，其特征是以神经元功能的丧失（包括帕金森氏病（PD）和Alzheimer's病（AD）的丧失。 Nurr1激活配体在AD和PD动物模型中显示出功能效率。然而，尽管核受体被认为是配体依赖性转录因子，但nurr1被认为功能独立于结合细胞中产生和存在的内源性配体。已经报道了激活Nurr1转录的几种合成配体，但大多数尚未验证以直接结合Nurr1，其作用机理仍然未知，这已经发达了为AD和PD优化Nurr1配体的努力。激活NURR1-RXR异二聚体转录的合成RXR配体在AD和PD动物模型中也显示出功能效率。然而，它仍然鲜为人知的RXR和RXR结合配体如何影响NURR1-RXR在结构水平上的功能。 In this project, we will address these knowledge gaps using mechanical studies to deﬁne how small molecule ligands impact Nurr1 and Nurr1-RXR activation on the molecular, structural, and cellular levels using NMR spectroscopy, X-ray crystallography, mass spectrometry coupled to hydrogen/deuterium exchange (HDX-MS) and chemical crosslinking (XL-MS) and small angle X-ray scattering along with生化和细胞功能测定。这些数据将为新的和改进的Nurr1激活配体的设计提供信息，以确定NurR1的直接靶向是否是通过RXR靶向的，是AD和PD处理的可行选择