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

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回路组成，其中clock1基因产物抑制其自身的转录。在实验室啮齿类动物模型中，大脑病变改变光照环境和定时营养限制对节律的实验性操纵可以影响肿瘤的生长和存活时间。研究表明，异常的昼夜节律性与癌症发展风险增加和诊断癌症患者生存统计数据下降有关。

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.