BIOSTATISTICS/ADMINISTRATIVE

生物统计/行政

• 批准号: 7254404
• 负责人: CLEMENT C IP
• 金额: $ 8.83万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254404
• 关键词: Address; Androgen Receptor; Androgen Suppression; Androgens; Apoptosis; Binding; Biometry; Cancer Control; Caring; Caspase; Clinical; Clinical Trials; Clonal Expansion; Complex; Depressed mood; Development; Disease; End Point; Event; FOXO1A gene; Finasteride; Gene Expression; Genes; Genetic Transcription; Goals; Human; Hypoxia; Incidence; Induction of Apoptosis; Intervention; Intervention Studies; Intervention Trial; Laboratories; Malignant neoplasm of prostate; Mediating; Medical; Molecular; Neoplasms; Numbers; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Patients; Personal Satisfaction; Phase; Play; Process; Proliferating; Prostate; Prostate Cancer Prevention Trial; Prostatectomy; Prostatic Intraepithelial Neoplasias; Proteins; Public Health; Randomized; Receptor Activation; Receptor Signaling; Reporting; Research; Research Design; Role; Selenium; Signal Pathway; Signal Transduction; Staging; Stanolone; Supplementation; Testing; Testosterone; Tissue Sample; Work; Xenograft Model; base; bench to bedside; cancer cell; cancer diagnosis; cancer risk; cost; men; novel; peroxiredoxin I; pressure; prevent; programs; prostate cancer prevention; receptor expression; restoration; transcription factor

The objective of the program project is to develop a novel mechanism-driven strategy for prostate cancer prevention. The approach is based on suppressing androgen signal transduction at two different steps simultaneously by using finasteride to inhibit the formation of dihydrotestosterone and selenium to reduce androgen receptor (AR) expression. The program is built along a bench-to-bedside paradigm and consists of three highly integrated projects. Project 1 is to delineate how finasteride and selenium work cooperatively to modulate certain molecular events in controlling the clonal expansion of prostate cancer cells. Special emphasis is placed on the functional analysis of key targets and pathways responsible for the induction of apoptosis following treatment with finasteride/selenium. Microenvironmental hypoxia is frequently seen in a colony of proliferating cancer cells due to abnormalities of the vasculature. It is well known that hypoxia produces a variety of molecular changes as a selective pressure for survival. There is recent evidence suggesting that hypoxia facilitates AR activation and the transcription of androgen-responsive genes. The above process is mediated by a redox-regulating protein called peroxiredoxin-1, or Prx1. Prx1 is preferentially elevated in prostatic intraepithelial neoplasia and prostate cancer cells. Project 2 is to investigate the mechanism of hypoxia/Prxl stimulation of AR signaling and to assess the role of Prx1 in modifying the cancer control efficacy of finasteride/selenium. The findings of Projects 1 and 2 are critical to the interpretation of the clinical trial results of Project 3. A short-term intervention trial is proposed to verify the effect of finasteride/selenium on androgen target gene expression and apoptosis induction in prostate tissue samples obtained from pre-prostatectomy patients. A second objective of the trial is to determine whether a high level of Prx1 diminishes the sensitivity to finasteride/selenium intervention. Every year, approximately 230,000 new cases of prostate cancer are diagnosed in the US, and some 30,000 men will die of this disease. As a public health problem, prostate cancer engenders huge medical care and human suffering costs. Blocking the progression of small volume, low-grade neoplasia is increasingly being recognized as an important aspect of prostate cancer control. Our goal is to find a way of managing the disease at an early stage in order to prevent it from becoming clinical relevant.

该项目的目标是开发一种新的机制驱动的前列腺癌的策略 预防该方法是基于在两个不同的步骤抑制雄激素信号转导 同时通过使用芬特来抑制双氢睾酮的形成和硒来减少 雄激素受体（AR）表达。该计划是建立在沿着一个板凳到床边的范例，并包括 三个高度融合的项目。项目1是描述芬迪和硒如何协同工作 以调节控制前列腺癌细胞克隆扩增的某些分子事件。特别 重点放在功能分析的关键目标和途径，负责诱导 用非那肽/硒处理后的细胞凋亡。微环境缺氧是常见的， 由于脉管系统的异常而导致的增殖癌细胞的集落。众所周知，缺氧 作为生存的选择压力产生了各种分子变化。最近有证据表明 表明缺氧促进AR激活和雄激素应答基因的转录。的 上述过程是由一种称为过氧化物氧还蛋白-1或Prx 1的氧化还原调节蛋白介导的。Prx 1是 在前列腺上皮内瘤变和前列腺癌细胞中优先升高。项目2是 研究缺氧/Prx 1刺激AR信号传导的机制，并评估Prx 1在 改变了非那肽/硒的癌症控制功效。项目1和项目2的结果对以下方面至关重要： 项目3临床试验结果的解释。建议进行短期干预试验以验证 非那雄胺/硒对前列腺雄激素靶基因表达及凋亡诱导作用 从前列腺切除术前患者获得的组织样品。审判的第二个目的是确定 高水平的Prx 1是否会降低对芬氟拉明/硒干预的敏感性。每年， 在美国，大约有230，000例新的前列腺癌病例被诊断出来，大约30，000名男性将被诊断出患有前列腺癌。 死于这种疾病。作为一个公共卫生问题，前列腺癌引起巨大的医疗保健和人类 痛苦的代价。阻止小体积、低级别肿瘤的进展越来越多地被 被认为是前列腺癌控制的重要方面。我们的目标是找到一种管理 在疾病的早期阶段，以防止它成为临床相关。