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，可介导稳态和病理学 人类激素反应系统的功能。自从最初的克隆以来，过去30年 雄激素受体cDNA，分子洞察雄激素受体功能，包括正常和病理， 从发现结合和调节雄激素受体活性的蛋白质的发现中获得了收集。这些 雄激素受体相互作用的蛋白质（更称为Arteractom）构成功能多样 在细胞水平上调节雄激素受体在空间和时间中调节雄激素受体功能的蛋白质的光谱。喜欢 其他性类替代激素受体家族成员，雄激素受体是一种非常粘的受体。它还有更多 比350个结合伴侣，这允许雄激素受体用作枢纽，以调节在 通过动态蛋白质与ARTERACTOME相互作用的分子水平。不幸的是，ar- 随着时间的流逝，Interactome继续增长，看不到明确的结局。我们无法在 单个细胞模型几乎无法实验复制Arteractome和 了解他们的协调作用如何调节时空中的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投机性的。我们的科学 前提是，细胞中AR-Interactom的仔细注释和发现将为 了解该亚蛋白质组如何促进生理和病理雄激素受体功能 激素反应系统。因此，我们提出了一个实验计划来注释Arteractome 在雄激素敏感的细胞模型中使用尖端的定量蛋白质组学技术。我们的蛋白质组学 方法将定义细胞中Ar-Interactome的时空图，并为探测奠定基础 蛋白质复合物内部和包括AR互联体之间的遗传关系。蛋白质组学 调查结果将使我们能够在细胞系统中开发可测试的AR依赖性信号传导模型。这些模型 将提供一个分子框架，以了解雄激素介导的信号如何在 稳态和病理状态。更重要的是，他们将指导发现新颖的可毒目标 在AR互联体中，可以在雄激素受体中衰减的AR依赖性信号传导 与人类中繁殖和非生殖系统相关的相关病理。