Ah Receptor Regulation of Prostate Tumor Progression
Ah 受体对前列腺肿瘤进展的调节
基本信息
- 批准号:6910037
- 负责人:
- 金额:$ 22.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-06-21 至 2007-05-31
- 项目状态:已结题
- 来源:
- 关键词:androgen receptoraromatic hydrocarbon receptorbiological signal transductioncancer preventioncell differentiationchromograninsgene expressiongenetic regulationgenetically modified animalsgenotypehistologyimmunocytochemistryindoleslaboratory mouselymph nodesneoplasm /cancer geneticsneoplastic processneuroendocrine systemneuropilinspolychlorodibenzofuranprostate neoplasmstransfection /expression vector
项目摘要
DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a transcription factor that binds chlorinated dioxins, other xenobiotics, and various endogenous chemicals and mediates their effects on gene expression in most organs, including prostate. We have discovered that the AhR signaling pathway can greatly affect the incidence of overt prostate cancer. Transgenic adenocarcinoma mouse prostate (TRAMP) mice on a C57BL/6J background rarely develop macroscopic prostate cancer (1 of 27 mice), but their heterozygous (Ahr +/-) and homozygous (Ahr -/-) AhR mutant TRAMP siblings rapidly develop large tumors (27 of 65 and 10 of 15 mice, respectively). Yet no tumors occur in Ahr +/- or Ahr -/- mice in the absence of the TRAMP transgene. These preliminary results demonstrate that the AhR can greatly affect the progression phase of prostate cancer, and suggest that Ahr may be a tumor suppressor gene. One objective of the proposed research is to elucidate mechanisms by which AhR regulates prostate tumor progression. Effects of Ahr genotype on microscopic and macroscopic prostate cancer development in TRAMP mice will be systematically determined. Hypotheses about the mechanisms responsible for these differences in tumor incidence will be tested by sequentially determining large T antigen, AhR, and androgen receptor expression in Ahr +/+, Ahr +/-, and Ahr -/- TRAMP mice. Loss of heterozygosity analysis on the AhR gene and measurements of androgen receptor gene allele number may also be conducted. The primary mechanistic objective is to test the hypothesis that Ahr genotype, controls prostate tumor progression by controlling neuroendocrine differentiation of prostatic cells. This hypothesis is based on preliminary results from gene expression analysis and immunohistochemical localization studies that neuroendocrine differentiation occurs before poorly differentiated nodules vascularize and therefore may be the key Ahr-regulated event that determines whether poorly differentiated lesions will vascularize and subsequently develop into large tumors. The final objective is to test the hypothesis that selective AhR modulators (SAhRMs) - 6-methyl- 1,3,8-trichlorodibenzofuran (6-MCDF) and indole- 3-carbinol - can inhibit or prevent prostate cancer. These experiments will use Ahr +/+TRAMP mice on the standard C57BL/6 x FVB background. Both SAhRMs inhibit prostate cancer cell proliferation in vitro. The proposed studies will elucidate the biochemical basis for effects of the AhR signaling pathway on prostate cancer and begin the in vivo testing of SAhRMs as a possible new therapeutic strategy for treating this disease. The potential impact on human health is that studies on this newly discovered prostate AhR regulatory mechanism in mice may shed light on AhR-related mechanisms capable of controlling prostate tumor progression (which determines whether men with prostate cancer live with or die from this disease) in humans
描述(由申请人提供):芳烃受体(AhR)是一种转录因子,可结合氯代二恶英、其他外源性物质和各种内源性化学物质,并介导其对大多数器官(包括前列腺)中基因表达的影响。我们已经发现AhR信号通路可以极大地影响明显的前列腺癌的发病率。C57 BL/6J背景的转基因腺癌小鼠前列腺(TRAMP)小鼠很少发生肉眼可见的前列腺癌(27只小鼠中的1只),但它们的杂合(Ahr +/-)和纯合(Ahr-/-)AhR突变体TRAMP同胞迅速发生大肿瘤(65只小鼠中的27只和15只小鼠中的10只)。然而,在不存在TRAMP转基因的情况下,在Ahr +/-或Ahr-/-小鼠中没有肿瘤发生。这些初步结果表明,AhR可以大大影响前列腺癌的进展阶段,并建议Ahr可能是一个肿瘤抑制基因。这项研究的目的之一是阐明AhR调节前列腺肿瘤进展的机制。将系统地确定Ahr基因型对TRAMP小鼠中显微镜和肉眼可见的前列腺癌发展的影响。将通过依次测定Ahr +/+、Ahr +/-和Ahr-/-TRAMP小鼠中的大T抗原、AhR和雄激素受体表达来检验有关肿瘤发生率差异机制的假设。也可以进行AhR基因杂合性缺失分析和雄激素受体基因等位基因数量的测量。主要的机制目标是检验Ahr基因型通过控制前列腺细胞的神经内分泌分化来控制前列腺肿瘤进展的假设。这一假说是基于基因表达分析和免疫组织化学定位研究的初步结果,即神经内分泌分化发生在低分化结节血管化之前,因此可能是决定低分化病变是否血管化并随后发展成大肿瘤的关键Ahr调节事件。最终目的是检验选择性AhR调节剂(SAhRM)-6-甲基-1,3,8-三氯二苯并呋喃(6-MCDF)和吲哚-3-甲醇-可以抑制或预防前列腺癌的假设。这些实验将在标准C57BL/6 x FVB背景下使用Ahr +/+ TRAMP小鼠。两种SAhRM均在体外抑制前列腺癌细胞增殖。拟议的研究将阐明AhR信号通路对前列腺癌的影响的生化基础,并开始SAhRM作为治疗这种疾病的可能的新治疗策略的体内测试。对人类健康的潜在影响是,在小鼠中对这种新发现的前列腺AhR调节机制的研究可能揭示人类中能够控制前列腺肿瘤进展的AhR相关机制(这决定了患有前列腺癌的男性是否患有这种疾病或死于这种疾病
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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RICHARD Eugene PETERSON其他文献
RICHARD Eugene PETERSON的其他文献
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{{ truncateString('RICHARD Eugene PETERSON', 18)}}的其他基金
Cellular and molecular mediators of fibrosis in the development of urinary tract dysfunction
尿路功能障碍发展过程中纤维化的细胞和分子介质
- 批准号:
10295668 - 财政年份:2021
- 资助金额:
$ 22.92万 - 项目类别:
Ah Receptor Regulation of Prostate Tumor Progression
Ah 受体对前列腺肿瘤进展的调节
- 批准号:
6725847 - 财政年份:2004
- 资助金额:
$ 22.92万 - 项目类别:
Ah Receptor Regulation of Prostate Tumor Progression
Ah 受体对前列腺肿瘤进展的调节
- 批准号:
7065199 - 财政年份:2004
- 资助金额:
$ 22.92万 - 项目类别:
AH RECEPTOR INDEPENDENT CNS/REPRODUCTIVE EFFECTS OF PCBS
PCBS 对 AH 受体的独立 CNS/生殖影响
- 批准号:
2155703 - 财政年份:1995
- 资助金额:
$ 22.92万 - 项目类别:
AH RECEPTOR INDEPENDENT CNS/REPRODUCTIVE EFFECTS OF PCBS
PCBS 对 AH 受体的独立 CNS/生殖影响
- 批准号:
2155704 - 财政年份:1995
- 资助金额:
$ 22.92万 - 项目类别:
AH RECEPTOR INDEPENDENT CNS/REPRODUCTIVE EFFECTS OF PCBS
PCBS 对 AH 受体的独立 CNS/生殖影响
- 批准号:
2684430 - 财政年份:1995
- 资助金额:
$ 22.92万 - 项目类别:
AH RECEPTOR INDEPENDENT CNS/REPRODUCTIVE EFFECTS OF PCBS
PCBS 对 AH 受体的独立 CNS/生殖影响
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- 资助金额:
$ 22.92万 - 项目类别:
TOXICOLOGY OF PERFLUORINATED FATTY ACID-LIPID CONJUGATES
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- 批准号:
3299231 - 财政年份:1989
- 资助金额:
$ 22.92万 - 项目类别:
TOXICOLOGY OF PERFLUORINATED FATTY ACID-LIPID CONJUGATES
全氟化脂肪酸-脂质缀合物的毒理学
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2180716 - 财政年份:1989
- 资助金额:
$ 22.92万 - 项目类别:
TOXICOLOGY OF PERFLUORINATED FATTY ACID-LIPID CONJUGATES
全氟化脂肪酸-脂质缀合物的毒理学
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3299232 - 财政年份:1989
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$ 22.92万 - 项目类别:
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