Regulation of Androgen Receptor Conformation

雄激素受体构象的调节

• 批准号: 7475692
• 负责人: JEREMY O JONES
• 金额: $ 5.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475692
• 关键词: Actin-Binding Protein; Actins; Affect; Androgen Antagonists; Androgen Receptor; Androgens; Biological Assay; Cancer cell line; Collection; Cytoskeleton; Dimerization; Dose; Estrogens; Fluorescence Resonance Energy Transfer; Genetic Transcription; Genetic screening method; Glucocorticoids; Grant; Growth; LIM Domain Kinase 1; Label; Libraries; Ligands; Malignant neoplasm of prostate; Mediating; Methods; Molecular Conformation; Nuclear Import; Nuclear Receptors; PC3 cell line; PPAR gamma; Pathway interactions; Peroxisome Proliferators; Pharmaceutical Preparations; Polymerase Chain Reaction; Prostate carcinoma; Publishing; Range; Regulation; Reporter; Reporter Genes; Role; Screening procedure; Signal Pathway; Signal Transduction; Somatotropin; Testing; Thyroid Gland; United States Food and Drug Administration; base; cancer cell; cross reactivity; established cell line; high throughput screening; human ESR1 protein; inhibitor/antagonist; kinase inhibitor; novel; novel therapeutics; nucleocytoplasmic transport; receptor; receptor function; response; rho; small molecule; therapeutic target

DESCRIPTION (provided by applicant): The androgen receptor (AR) is a nuclear receptor that is the primary therapeutic target of prostate cancer (CaP). This grant concerns characterization of a cellular pathway that regulates AR activity, which could produce new therapeutic targets, and the application of a novel screening strategy to identify small molecules that inhibit AR function. We hypothesize that the Rho/ROCK/LIM kinase (RRL) pathway regulates AR activity through alterations in the actin cytoskeleton. I will use prostate carcinoma lines that stably express native and fluorescently-labeled AR to determine how the RRL pathway influences the folding, dimerization, nuclear import, and transcriptional activity of AR. We also hypothesize that compounds that inhibit AR ligand-induced conformational change may reveal novel anti-androgens that would be missed by traditional screens for AR inhibitors. I will use a high-throughput FRET assay to screen three collections of biologically active small molecules for compounds that inhibit AR ligand-induced conformational change. The most effective inhibitors will be examined in detailed secondary analyses to determine their effect on AR nuclear transport, dimerization, native AR-responsive transcription, and proliferation of prostate cancer cells.

描述（由申请人提供）：雄激素受体（AR）是一种核受体，是前列腺癌（CaP）的主要治疗靶点。该资助涉及调节AR活性的细胞途径的表征，这可能产生新的治疗靶点，以及一种新的筛选策略的应用，以识别抑制AR功能的小分子。我们推测Rho/ROCK/LIM激酶（RRL）通路通过改变肌动蛋白细胞骨架来调节AR活性。我将使用稳定表达天然和荧光标记AR的前列腺癌细胞系来确定RRL途径如何影响AR的折叠、二聚化、核输入和转录活性。我们还假设，抑制AR配体诱导的构象变化的化合物可能会揭示新的抗雄激素，这将被传统的AR抑制剂筛选所遗漏。我将使用高通量FRET检测筛选三个生物活性小分子的集合，以抑制AR配体诱导的构象变化的化合物。将在详细的二次分析中检查最有效的抑制剂，以确定其对AR核转运、二聚化、天然AR应答转录和前列腺癌细胞增殖的影响。