Regulation of Androgen Receptor Conformation
雄激素受体构象的调节
基本信息
- 批准号:7152772
- 负责人:
- 金额:$ 4.6万
- 依托单位:
- 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:
- 关键词:
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(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。这项拨款涉及调节AR活性的细胞途径的特征,这可能产生新的治疗靶点,以及应用一种新的筛选策略来识别抑制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AR和荧光标记AR的前列腺癌株来确定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揭示出传统AR抑制剂筛选所遗漏的新的抗雄激素。我将使用高通量FRET分析来筛选三个具有生物活性的小分子集合,以寻找抑制AR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二次分析中进行检验,以确定它们对AR核运输、二聚化、天然AR反应转录和前列腺癌细胞增殖的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JEREMY O JONES其他文献
JEREMY O JONES的其他文献
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{{ truncateString('JEREMY O JONES', 18)}}的其他基金
Ligand-Independent Selective Modulation of Androgen Receptor Activity
雄激素受体活性的配体独立选择性调节
- 批准号:
8319654 - 财政年份:2010
- 资助金额:
$ 4.6万 - 项目类别:
Ligand-Independent Selective Modulation of Androgen Receptor Activity
雄激素受体活性的配体独立选择性调节
- 批准号:
8137043 - 财政年份:2010
- 资助金额:
$ 4.6万 - 项目类别:
Ligand-Independent Selective Modulation of Androgen Receptor Activity
雄激素受体活性的配体独立选择性调节
- 批准号:
8109620 - 财政年份:2010
- 资助金额:
$ 4.6万 - 项目类别:
Ligand-Independent Selective Modulation of Androgen Receptor Activity
雄激素受体活性的配体独立选择性调节
- 批准号:
7638779 - 财政年份:2009
- 资助金额:
$ 4.6万 - 项目类别:
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