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Biochemical, structural and molecular dissection of androgen receptor transcriptional activity

雄激素受体转录活性的生化、结构和分子剖析

基本信息

批准号：
10655002
负责人：
Elizabeth Victorina Wasmuth
金额：
$ 24.9万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655002
关键词：
Affinity Androgen Antagonists Androgen Receptor Androgen-Insensitivity Syndrome Androgens Architecture Atomic Force Microscopy Binding Biochemical Biological Biological Assay Biology Cancer Biology Cell Line Cells Cellular Morphology ChIP-seq Chromatin Communication Complex Consensus Cryoelectron Microscopy DNA DNA Binding DNA Binding Domain Development Dimerization Disease Dissection Drug Targeting Electron Microscopy Electrons Etiology Generations Genetic Transcription Global Change Glucocorticoid Receptor Goals Growth Health In Vitro Joints Kennedy Syndrome Knowledge Laboratories Leadership Lentivirus Ligand Binding Domain Maintenance Male Pattern Baldness Malignant neoplasm of prostate Mediating Memorial Sloan-Kettering Cancer Center Metastatic Prostate Cancer Metastatic to Methods Mineralocorticoid Receptor Modeling Molecular Molecular Conformation Mutate Mutation N-terminal National Institute of General Medical Sciences Negative Staining Nuclear Hormone Receptors Nucleoproteins Output Phenotype Phenotypic Sex Process Progesterone Receptors Prostate Proteins Receptor Activation Receptor Inhibition Receptor Signaling Recombinant Proteins Recombinants Regulation Reporter Reporting Research Research Personnel Resolution Running Sex Differentiation Sexual Development Site Stanolone Structural Models Structure Surface System Testing Testosterone Training Transactivation Transcript Transcriptional Regulation Universities Ursidae Family Validation Variant Work X-Ray Crystallography base career castration resistant prostate cancer cell growth cofactor computerized data processing data acquisition design enzalutamide experience flexibility functional outcomes genetic corepressor human disease improved in vivo inhibitor innovation insight male mutant novel particle post-doctoral training prostate cancer cell protein protein interaction receptor binding skills structural biology three-dimensional modeling transcription factor transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY AND ABSTRACT The androgen receptor (AR) is the master transcription factor responsible for development and maintenance of the male sex phenotype. Aberrant AR activity is associated with multiple disorders, including but not limited to metastatic prostate cancer, androgenetic alopecia, and Kennedy's disease. Cell-based studies have reported AR is regulated through numerous processes, including 1) androgen stimulation; 2) anti-androgen inhibition; 3) intramolecular contacts among its domains; 4) association with various protein coactivators and corepressors. Despite its importance in disease etiology, the mechanistic details underlying AR regulation are largely unknown due to historical difficulty isolating pure, active multidomain AR variants. This research will employ biochemical and complementary structural methods – including electron and atomic force microscopy, and x-ray crystallography – to illuminate the molecular determinants of AR activation through identification of surfaces important for intramolecular and cofactor-mediated stimulation (Aim 1), and for AR inhibition by anti-androgen binding and self-regulatory modes of autoinhibition (Aim 3). The molecular details revealed by the biochemical and structural studies will be validated in biologically relevant AR-dependent cell lines to determine the functional outcomes of these interactions on cell morphology, growth, AR signaling and the AR cistrome (Aim 2). The findings from these studies will provide novel insight for modes of dimerization, intramolecular regulation, and DNA binding for AR as well as other type I nuclear hormone receptors, including the progesterone, glucocorticoid, and mineralocorticoid receptors, and can facilitate potential design of novel AR-targeting drugs. This research is in line with the goals of the NIGMS of generating fundamental knowledge that will bear implication for human disease and health. The comprehensive training plan described will enable the investigator to achieve her career goals of running an independent academic laboratory dedicated to studying fundamental modes of AR transcriptional regulation in the context of its active, hyperactivated, and inhibited states, and will provide biochemical, structural, and functional insight to the consequences of its aberrant activity in disease. As a joint mentee in top prostate cancer and structural biology laboratories at Memorial Sloan Kettering Cancer Center and the Rockefeller University, she will receive diverse training in prostate biology and electron microscopy that will expand the investigator's biological understanding and technical repertoire that will enable significant innovation in her future research. The leadership, networking, and communication skills she will acquire through the MOSAIC UE5 will facilitate her transition to independence, and equip her to enhance diversity in the scientific workforce.

项目总结和摘要雄激素受体（AR）是负责发育和维持的主要转录因子，男性性别表型。异常AR活性与多种疾病相关，包括但不限于转移性前列腺癌、雄激素性脱发和肯尼迪病。基于细胞的研究报告说， AR通过许多过程调节，包括1）雄激素刺激; 2）抗雄激素抑制; 3）其结构域之间的分子内接触; 4）与各种蛋白质共激活子和共阻遏子的缔合。尽管其在疾病病因学中的重要性，但AR调节的机制细节在很大程度上是未知的。由于分离纯的、活性多结构域AR变体的历史困难而未知。这项研究将采用生物化学和互补结构的方法-包括电子和原子力显微镜和X射线晶体学-通过以下方式阐明AR激活的分子决定因素：识别对分子内和辅因子介导的刺激（Aim 1）以及AR重要的表面通过抗雄激素结合和自我抑制的自我调节模式进行抑制（目的3）。的分子层析的细节将在生物学相关的AR依赖性细胞中验证生物化学和结构研究所揭示的细胞系，以确定这些相互作用对细胞形态、生长、AR信号传导和 AR顺反子（Aim 2）。这些研究的发现将为二聚化模式提供新的见解，分子内调节和AR以及其他I型核激素受体的DNA结合，包括孕酮、糖皮质激素和盐皮质激素受体，并且可以促进潜在的设计新的 AR靶向药物这项研究符合NIGMS产生基础知识的目标这将对人类疾病和健康产生影响。所描述的全面培训计划将使调查员能够实现她的职业目标，一个独立的学术实验室，致力于研究AR转录调控的基本模式在其活性，超活化和抑制状态的背景下，并将提供生物化学，结构，功能洞察其异常活动的疾病后果。作为一个联合学员在顶部前列腺纪念斯隆-凯特琳癌症中心和洛克菲勒中心的癌症和结构生物学实验室大学期间，她将接受前列腺生物学和电子显微镜方面的各种培训，研究人员的生物学理解和技术技能，将使她的重大创新，未来的研究。她将通过MOSAIC获得的领导力、网络和沟通技能 UE 5将促进她向独立的过渡，并使她能够增强科学劳动力的多样性。