Towards the discovery of Nurr1-RXR modulators

致力于发现 Nurr1-RXR 调制器

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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.

核受体转录因子Nurr 1对于调节和维持几种细胞因子是必需的。 哺乳动物大脑发育和体内平衡的重要方面。Nurr 1调节基因程序， 控制多巴胺能神经元的发育和功能，这对运动神经元的功能至关重要 帕金森病患者的退化的运动和控制。此外，最近的研究 显示Nurr 1是调节神经炎症和淀粉样蛋白β积累重要因子 阿尔茨海默病患者的发病机制中发生的Aβ。这些和其他研究表明， Nurr 1的分子活化作为阿尔茨海默病，帕金森病， 以及其它以神经元丧失为特征的衰老相关神经变性和痴呆病症 功能然而，发现Nurr 1结合和/或转录激活小的筛选活动， 分子已经产生了有限的Nurr 1特异性化合物支架，并且还没有提供有效的，高的 亲和Nurr 1特异性配体。另一种调节Nurr 1活性的方法已经获得了动力， 通过与RXR LBD结合的小分子配体靶向Nurr 1-RXR异二聚体复合物。在这 项目，我们将建立在我们强大的初步数据和开发生化和细胞检测， 配体诱导的Nurr 1-RXR活性变化。我们研究的成功成果将提供一个平台， 筛选，发现和表征Nurr 1-RXR选择性配体，可用作研究的化学工具 阿尔茨海默病、帕金森病和其他衰老相关疾病模型中的Nurr 1-RXR调节 神经变性和痴呆症。