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: 7683269
• 负责人: ALEC J DAVIDSON
• 金额: $ 19.25万
• 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/7683269
• 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，由此clock 1基因产物抑制其自身的转录。在实验室啮齿动物模型中，通过脑损伤、改变光照环境和定时营养限制来实验性操纵节律可以影响肿瘤生长和存活时间。已经表明，异常的昼夜节律性与癌症发展的风险增加以及与诊断的癌症患者的存活率统计减少相关。 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，我们建议说明时空 健康前列腺和前列腺癌中基因表达的昼夜节律动力学。我们还将 检查暂时限制的营养是否调节前列腺节律和肿瘤发生， 进展 具体目标1：通过体外和体内追踪生物发光报告基因，评价前列腺癌与健康前列腺组织相比是否改变了基因表达的昼夜节律。我们将产生一个双转基因小鼠，发展前列腺癌和表达Per 2：荧光素酶融合蛋白和表征mPer 2基因的时间表达谱在前列腺上皮内瘤（PIN），前列腺腺癌，转移灶和健康的周围组织。与此同时，我们将开发一种致瘤性前列腺癌细胞系，与C57 BL/6同源，表达昼夜荧光素酶报告基因，以允许在麻醉小鼠中体内跟踪肿瘤生长和肿瘤中的分子节律，并最终在清醒的行为小鼠中。 具体目标2：检验昼夜节律的营养调控差异 影响肿瘤发展我们将使具有生物发光肿瘤的双转基因小鼠或其WT同窝出生的小鼠暴露于已知改变外周器官中的分子和生理节律的营养操作：白天限制进食，夜间限制进食，以及作为对照的无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发展和进展。同时，我们将评估每种昼夜节律操作对原发性前列腺癌不同阶段、健康前列腺和皮下生物发光前列腺癌细胞中生物钟基因表达模式的影响。