Regulation of Androgen Receptor Conformation

雄激素受体构象的调节

• 批准号: 7152772
• 负责人: JEREMY O JONES
• 金额: $ 4.6万
• 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/7152772
• 关键词: actins; androgen receptor; androgens; carcinoma; cell line; conformation; library; ligands; neoplastic cell; nuclear receptors; prostate; prostate neoplasms; reporter genes; small molecule

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）的主要治疗靶标。该赠款涉及调节AR活性的细胞途径的表征，该途径可能产生新的治疗靶标，以及应用新颖的筛选策略来鉴定抑制AR功能的小分子。我们假设RHO/ROCK/LIM激酶（RRL）途径通过肌动蛋白细胞骨架的改变来调节AR活性。我将使用稳定表达天然和荧光标记的AR的前列腺癌系来确定RRL途径如何影响AR的折叠，二聚化，核进口和转录活性。我们还假设，抑制AR配体诱导构象变化的化合物可能会揭示出新型的抗雄激素，而传统屏幕会为AR抑制剂遗漏。我将使用高通量的FRET分析来筛选三个集合的生物活性小分子，以抑制配体诱导的构象变化的化合物。最有效的抑制剂将在详细的次级分析中进行检查，以确定其对AR核转运，二聚化，天然AR反应性转录和前列腺癌细胞增殖的影响。