MSM/WCI Partnership To Investigate Mechanisms Of Prostate Cancer (1 Of 2)

MSM/WCI 合作研究前列腺癌的机制（2 中的 1）

• 批准号: 7410225
• 负责人: ALEC J DAVIDSON
• 金额: $ 18.5万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-29 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7410225
• 关键词: MSM; WCI; Partnership; Investigate; Mechanisms

DESCRIPTION (provided by applicant): The molecular machinery that governs circadian rhythmicity is comprised of transcriptional translational feedback loop whereby clock1 gene products inhibit their own transcription. Experimental manipulation of rhythms by brain lesions altered lighting environments and timed nutritional restriction can affect tumor growth and survival times in laboratory rodent models. It has been shown that aberrant circadian rhythmicity correlates with an increased risk of cancer development and with decreased survival statistics in diagnosed cancer patients. Using newly developed bioluminescent mouse tumor models, bioluminescent prostate cancer cell lines, and newly-developed in vivo molecular imaging techniques, we propose to illustrate the spatiotemporal dynamics of circadian rhythms of gene expression in healthy prostate and prostate cancer. We will also examine whether temporally restricted nutrition regulates prostate rhythmicity, and tumorigenesis and progression. Specific Aim 1: To evaluate whether prostate cancers have altered circadian rhythms of gene expression compared with healthy prostate tissue via in vitro and in vivo tracking of bioluminescent reporter genes. We will generate a dual transgenic mouse that develops prostate cancer and expresses the Per2:luciferase fusion protein and characterize the mPer2 gene temporal expression profile in prostate intraepithelial neoplasia (PIN), prostate adenocarcinoma, and metastatic foci and in healthy surrounding tissue. In parallel, we will develop a tumorigenic prostate cancer cell line, syngeneic on C57BL/6, which expresses circadian luciferase reporter genes to allow for in vivo tracking of tumor growth and molecular rhythms in tumors in anesthetized mice, and eventually in awake, behaving mice. Specific Aim 2: To test the hypothesis that nutritional manipulations of circadian rhythms differentially affect tumor development We will expose the dual transgenic mice or their WT littermates with bioluminescent tumors to nutritional manipulations known to alter molecular and physiological rhythmicity in peripheral organs: daytime restricted feeding, nighttime restricted feeding, and, as a control, caloric restriction without circadian entrainment. Tumor development and progression will be assessed longitudinally in mouse via in vivo imaging of tumor volume. In parallel, we will assess the effects of each circadian manipulation on circadian clock gene expression patterns in various stages of primary prostate cancer, in healthy prostate gland and in subcutaneous bioluminescent prostate adenocarcinoma cells.

描述（由申请人提供）：控制昼夜节律的分子机制由转录翻译反馈环组成，其中clock1基因产物抑制其自身转录。通过脑损伤改变照明环境和定时营养限制来控制节律的实验可以影响实验室啮齿动物模型中的肿瘤生长和生存时间。研究表明，异常的昼夜节律与癌症发展风险增加以及诊断癌症患者的生存统计数据下降相关。 使用新开发的生物发光小鼠肿瘤模型、生物发光前列腺癌细胞系， 和新开发的体内分子成像技术，我们建议阐明时空 健康前列腺和前列腺癌中基因表达的昼夜节律动态。我们还将 检查暂时限制营养是否调节前列腺节律和肿瘤发生 进展。 具体目标 1：通过生物发光报告基因的体外和体内跟踪，评估与健康前列腺组织相比，前列腺癌是否改变了基因表达的昼夜节律。我们将产生一种双转基因小鼠，其发展为前列腺癌并表达 Per2：荧光素酶融合蛋白，并表征前列腺上皮内瘤变 (PIN)、前列腺腺癌和转移灶以及健康周围组织中的 mPer2 基因时间表达谱。与此同时，我们将开发一种与 C57BL/6 同源的致瘤性前列腺癌细胞系，它表达昼夜节律荧光素酶报告基因，以便在麻醉小鼠以及最终清醒、行为正常的小鼠中体内跟踪肿瘤生长和分子节律。 具体目标 2：检验昼夜节律的营养控制存在差异的假设 影响肿瘤发展我们将把带有生物发光肿瘤的双转基因小鼠或其WT同窝小鼠暴露于已知会改变外周器官分子和生理节律的营养操作中：白天限制进食，夜间限制进食，以及作为对照，不带昼夜节律的热量限制。将通过肿瘤体积的体内成像在小鼠中纵向评估肿瘤的发生和进展。与此同时，我们将评估每种昼夜节律操作对原发性前列腺癌、健康前列腺和皮下生物发光前列腺癌细胞各个阶段的生物钟基因表达模式的影响。