Construction of the Androgen Receptor Interactome: A Molecular Framework for Probing Genetic Interactions in Androgen-Dependent Signaling

雄激素受体相互作用组的构建：探测雄激素依赖性信号传导中遗传相互作用的分子框架

• 批准号: 10798627
• 负责人: Michael E Wright
• 金额: $ 13.14万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798627
• 关键词: Androgen Receptor; Androgens; Attenuated; Behavior; Binding; Binding Proteins; Biochemical; Biological Assay; Biomedical Research; Biotin; Castration; Cell model; Cells; Cloning; Color; Communication; Communities; Complementary DNA; Coupled; Darkness; Data; Data Set; Disease; Family member; Foundations; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genomics; Glean; Goals; Gonadal Steroid Hormones; Health; Hormone Responsive; Human; Kinetics; Knowledge; LNCaP; Label; Length; Life; Ligand Binding Domain; Ligands; Ligation; Light; Maps; Mass Spectrum Analysis; Mediating; Mission; Modeling; Molecular; Molecular Probes; Molecular Structure; Motor Neurons; Musculoskeletal System; Nature; Nuclear Hormone Receptors; Organ; Organism; Outcome; Pancreas; Pathologic; Pathology; Pathway interactions; Physiological; Prostate; Prostatic Neoplasms; Protein Dynamics; Proteins; Proteomics; Public Health; Qualifying; RIPK1 gene; RIPK3 gene; RNA Splicing; Receptor Activation; Receptor Signaling; Research; Research Proposals; Resistance; Resolution; Resources; Signal Transduction; System; Techniques; Testing; Testis; Time; Tissues; United States National Institutes of Health; Variant; Vision; androgen sensitive; cellular development; disability; druggable target; guided inquiry; insight; new therapeutic target; non-genomic; novel; predictive modeling; prostate cancer cell; protein complex; protein protein interaction; receptor; receptor function; reproductive; reproductive organ; response; spatiotemporal; spinal and bulbar muscular atrophy; steroid hormone receptor; transmission process

Androgen receptor is a powerful sex-steroid hormone receptor that mediates homeostatic and pathological functions in hormone-responsive systems in humans. Over the past 30 years, since the original cloning of the androgen receptor cDNA, molecular insights into androgen receptor function, both normal and pathological, have been gleaned from the discovery of proteins that bind and regulate androgen receptor activity. These androgen receptor-interacting proteins, better known as the AR-interactome, constitute a functionally diverse spectrum of proteins that modulate androgen receptor function in space and time at the cellular level. Like other sex-steroid hormone receptor family members, androgen receptor is a very sticky receptor. It has more than 350 binding partners, which allows androgen receptor to serve as a hub to regulate cellular signaling at the molecular level through dynamic protein interactions with the AR-interactome. Unfortunately, the AR- interactome continues to grow over time with no clear end in sight. Our inability to define the AR-interactome in a single cellular model has made it nearly impossible to experimentally replicate the AR-interactome and understand how their coordinated actions regulate AR-dependent signaling in space and time. Thus, quantitative and predictive models of AR-dependent signaling remain speculative at best. Our scientific premise is that the careful annotation and discovery of the AR-interactome in cells will lay the foundation for understanding how this subproteome contributes to physiologic and pathologic androgen receptor functions in hormone-responsive systems. Thus, we have proposed an experimental plan to annotate the AR-interactome in androgen-sensitive cellular models using cutting-edge, quantitative proteomic techniques. Our proteomic approaches will define a spatiotemporal map of the AR-interactome in cells, and lay the foundation for probing genetic relationships within and between protein complexes comprising the AR-interactome. The proteomic findings will allow us to develop testable models of AR-dependent signaling in cellular systems. These models will provide a molecular framework to understand how androgen-mediated signaling operates under homeostatic and pathological states. More importantly, they will guide the discovery of novel druggable targets among the AR-interactome so that corrupted AR-dependent signaling can be attenuated in androgen receptor- related pathologies that afflict reproductive and non-reproductive systems in humans.

雄激素受体是一种强大的性类固醇激素受体，可介导体内平衡和病理学 在人类激素反应系统中发挥作用。自从最初的克隆以来，30年来 雄激素受体 cDNA，对雄激素受体功能（正常和病理）的分子见解， 是从结合和调节雄激素受体活性的蛋白质的发现中收集到的。这些 雄激素受体相互作用蛋白，更广为人知的是 AR 相互作用组，构成了功能多样的 在细胞水平上在空间和时间上调节雄激素受体功能的蛋白质谱。喜欢 其他性类固醇激素受体家族成员，雄激素受体是一种非常粘性的受体。它还有更多 超过 350 个结合伙伴，使雄激素受体能够作为调节细胞信号传导的枢纽 通过与 AR 相互作用组的动态蛋白质相互作用，在分子水平上进行研究。不幸的是，AR- 相互作用组随着时间的推移持续增长，目前还看不到明确的终点。我们无法定义 AR 交互组 单一细胞模型几乎不可能通过实验复制 AR 相互作用组，并且 了解它们的协调行动如何在空间和时间上调节 AR 依赖性信号传导。因此， AR 依赖性信号传导的定量和预测模型充其量仍然是推测性的。我们的科学 前提是细胞中 AR 相互作用组的仔细注释和发现将为 了解该亚蛋白质组如何促进雄激素受体的生理和病理功能 激素反应系统。因此，我们提出了一个实验计划来注释 AR-interactome 使用尖端的定量蛋白质组学技术在雄激素敏感的细胞模型中进行研究。我们的蛋白质组学 方法将定义细胞中 AR 相互作用组的时空图，并为探索奠定基础 构成 AR 相互作用组的蛋白质复合物内部和之间的遗传关系。蛋白质组学 研究结果将使我们能够开发细胞系统中 AR 依赖性信号传导的可测试模型。这些型号 将提供一个分子框架来了解雄激素介导的信号传导如何在 稳态和病理状态。更重要的是，它们将指导新型药物靶点的发现 AR-相互作用组之间的相互作用，因此雄激素受体中受损的 AR 依赖性信号传导可以减弱 - 影响人类生殖和非生殖系统的相关病理。