Regulation of Androgen Receptor Conformation

雄激素受体构象的调节

基本信息

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
项目类别：
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

项目摘要

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。