Implementation Stage

执行 试点项目#1：前列腺癌基因表达昼夜节律的时空动态 项目PI：Alec J. Davidson博士，莫尔豪斯医学院助理教授 项目PI：Chia-Ling Hsieh，Ph.D.，埃默里医学院助理教授 摘要 昼夜节律性为许多分子、细胞和生物学过程提供了至关重要的时间框架。 有机体的功能。直到最近，人们还认为哺乳动物的昼夜节律是由 大脑中的一个“主振荡器”，SCN。我们现在知道几乎所有的细胞和组织都有 能够产生昼夜节律的分子机制。最近的几份报告表明， 宿主昼夜节律的实验操作影响啮齿类动物的肿瘤生长和死亡率 癌在人类中，有迹象表明，昼夜节律的改变与癌症的风险相关， 确诊患者的生存率统计。因此，昼夜节律在宿主和肿瘤细胞中所起的作用 在癌症的发展和进展中的作用是非常有趣的。 前列腺癌是美国男性癌症相关死亡的第二大原因[35]。 此外，前列腺癌是所有健康风险中最大的种族差异之一。更好 治疗方法和机制的见解，关于这种疾病的发展和进展， 对科学界和社会都有很高的价值。 限制摄食时间表使行为、生理和基因的昼夜节律同步 在消化器官中表达，也显示抑制格拉斯哥骨肉瘤的生长， 小鼠的相关死亡率。因此，我们提出了一个项目，以更好地了解影响 限制喂养时间表对癌症发展和进展的影响，以及对肿瘤节律性的影响。 前列腺我们将开发一种新的小鼠模型和新的细胞系来研究分子昼夜节律的作用 前列腺癌的发生和发展的节律。将产生表达mPer 2Luc的小鼠， 生物发光昼夜报道基因，和TRAMP，前列腺特异性病毒癌基因，使分子 可以从癌症的每个阶段的良性和恶性组织实时评估节律性 进展此外，我们将开发新的前列腺细胞系，表达昼夜报道基因， 由生物钟驱动的前列腺癌生物发光可以在体内非侵入性地可视化。 这些方法共同构成了一个实验性的杰作，可以用来产生重要的新的 深入了解昼夜节律在前列腺癌中所起的作用，并将解决这一假设， 外周结构的节律性与生物体对抗发育的能力密切相关， 癌症的进展。这些实验将为今后研究 昼夜节律影响这种癌症和其他癌症的发展。

Implementation Pilot Project #1: Spatiotemporal dynamics of circadian rhythms of gene expression in prostate cancer Project PI: Alec J. Davidson Ph.D., Assistant Professor, Morehouse School of Medicine Project PI: Chia-Ling Hsieh, Ph.D., Assistant Professor, Emory School of Medicine Abstract Circadian rhythmicity provides a critically important temporal framework for many molecular, cellular and organismal functions. Until recently, it was thought that circadian rhythms in mammals were generated by a single 'master oscillator' in the brain, the SCN. We now know that virtually all cells and tissues have molecular machinery capable of generating circadian rhythms. Several recent reports suggest that experimental manipulation of host circadian rhythmicity affects tumor growth and mortality in rodents with cancer. In humans there are indications that altered circadian rhythmicity correlates with risk of cancer and with survival statistics in diagnosed patients. Therefore, the role played by circadian rhythms in host and tumor cells in the development and progression of cancer is of great interest. Prostate cancer is the second leading cause of cancer-related death in men in the United States [35]. Furthermore, prostate cancer represents one of the largest racial disparities among all risks to health. Better treatment approaches and mechanistic insight regarding the development and progression of this disease are of high value to both the scientific community and to society. Restricted feeding schedules synchronize circadian rhythms in behavior, physiology and gene expression in digestive organs and were also shown to inhibit growth of Glasgow osteosarcoma and to slow associated mortality in mice. Therefore, we propose a project to develop a better understanding of the impact of restricted feeding schedules on cancer development and progression, and on tumor rhythmicity in the prostate gland. We will develop a new mouse model and new cell lines to study the role of molecular circadian rhythms in the ontogeny and progression of prostate cancer. Mice will be generated that express mPer2Luc, a bioluminescent circadian reporter gene, and TRAMP, a prostate-specific viral oncogene, so that molecular rhythmicity can be assessed in real-time from benign and malignant tissue of every stage of cancer progression. Furthermore, we will develop new prostatic cell lines that express circadian reporter genes, so that prostate cancer bioluminescence driven by the circadian clock can be visualized non-invasively in vivo. These approaches together form an experimental tour de force that can be used to generate significant new insight into the roles played by circadian rhythmicity in prostate cancer and will address the hypothesis that rhythmicity in peripheral structures is intimately related to the organism's ability to combat the development and progression of cancer. The experiments will form the basis for future study of the mechanisms by which circadian rhythms influence the development of this and other cancers.