Towards the discovery of Nurr1-RXR modulators

致力于发现 Nurr1-RXR 调制器

基本信息

批准号：
10750409
负责人：
Douglas Kojetin
金额：
$ 43.24万
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：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750409
关键词：
Affect Affinity Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Antibodies Binding Biochemical Biological Assay Brain Cells Cellular Assay Chemicals Complement Complex Data Dementia Development Disease Dissociation Fluorescence Resonance Energy Transfer Future Genes Genetic Transcription Goals Heterodimerization Homeostasis Human Libraries Ligand Binding Ligands Maintenance Measures Modeling Movement NR4A2 gene Nerve Degeneration Neurodegenerative Disorders Nuclear Receptors Outcome Oxygen Parkinson Disease Pathogenesis Patients Pharmaceutical Chemistry Proteins RXR Regulation Research Personnel Signal Transduction Specificity Structure Testing Therapeutic Time Translating Work abeta accumulation detection assay dopaminergic neuron drug discovery drug-like compound high throughput screening member monomer motor neuron function neuroinflammation neuron loss novel pharmacologic programs protein protein interaction reconstitution recruit scaffold screening small molecule statistics synthetic drug tool transcription factor

项目摘要

The nuclear receptor transcription factor Nurr1 is essential for the regulation and maintenance of several important aspects of mammalian brain development and homeostasis. Nurr1 regulates a gene program that controls the development and function of dopaminergic neurons, which are critical for motor neuron function and control of movement that degenerates in patients with Parkinson’s disease. Furthermore, recent studies show that Nurr1 is an important factor in regulation of neuroinflammation and the accumulation of Amyloid beta (Aβ) that occurs in the pathogenesis of Alzheimer’s disease patients. These and other studies implicate small molecule activation of Nurr1 as a potential therapeutic strategy in Alzheimer’s disease, Parkinson’s disease, and other aging-associated neurodegenerative and dementia disorders characterized by a loss of neuron function. However, screening campaigns to discover Nurr1 binding and/or transcriptionally activating small molecules have produced limited Nurr1-specific compound scaffolds and have not yet provided potent, high affinity Nurr1-specific ligands. An alternative approach to regulate Nurr1 activity that has gained momentum is targeting Nurr1-RXR heterodimer complexes via small molecule ligands that bind to the RXR LBD. In this project, we will build on our strong preliminary data and develop biochemical and cellular assays that detect ligand-induced changes in Nurr1-RXR activity. The successful outcomes of our studies will provide a platform to screen, discover, and characterize Nurr1-RXR selective ligands that can be used as chemical tools to study Nurr1-RXR modulation in models of Alzheimer’s disease, Parkinson’s disease, and other aging-associated neurodegenerative and dementia disorders.

核接收器转录因子Nurr1对于调节和维护几个至关重要哺乳动物大脑发育和稳态的重要方面。 NURR1调节一个基因程序控制多巴胺能神经元的发育和功能，这对于运动神经元功能至关重要控制帕金森氏病患者的运动的控制。此外，最近的研究表明Nurr1是调节神经炎症和淀粉样蛋白β的积累的重要因素（Aβ）发生在阿尔茨海默氏病患者的发病机理中。这些和其他研究暗示很小 Nurr1的分子激活是阿尔茨海默氏病的潜在治疗策略，帕金森氏病，以及其他与神经元丧失为特征的与衰老相关的神经退行性和痴呆症功能。但是，筛选活动以发现Nurr1绑定和/或转录激活小分子产生了有限的NURR1特异性化合物支架，尚未提供潜力，很高亲和力nurr1特异性配体。一种调节NURR1活性的替代方法是通过与RXR LBD结合的小分子配体靶向Nurr1-RXR异二聚体复合物。在这个项目，我们将基于我们强大的初步数据，并开发出检测的生化和细胞测定法配体诱导的NURR1-RXR活性的变化。我们研究的成功结果将提供一个平台筛选，发现和表征Nurr1-RXR选择性配体，可以用作化学工具 NURR1-RXR在阿尔茨海默氏病，帕金森氏病和其他与衰老相关的模型中调节神经退行性和痴呆症疾病。