Implementation Stage

实施 试点项目1：前列腺癌基因表达昼夜节律的时空动力学 项目PI：Alec J.Davidson博士，莫尔豪斯医学院助理教授 PI项目：谢家玲博士，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 大脑中只有一个“主振荡器”，即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械。最近的几份报告表明 宿主昼夜节律的实验操纵影响啮齿动物肿瘤的生长和死亡率 癌症。在人类中，有迹象表明昼夜节律改变与患癌症的风险相关，并与 确诊患者的生存统计。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引起了极大的兴趣。 前列腺癌是美国男性癌症相关死亡的第二大原因。 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 关于这种疾病的发展和进展的治疗方法和机制的洞察是 对科学界和社会都有很高的价值。 限制进食时间表在行为、生理和基因上同步昼夜节律 在消化器官中的表达，也被证明对格拉斯哥骨肉瘤的生长有抑制和减缓作用 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 限制进食时间表对癌症的发展和进展，以及对肿瘤节律性的影响 前列腺癌。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 前列腺癌个体发生和进展的节律。小鼠将表达mPer2Luc，a 生物发光昼夜节律报告基因，以及前列腺特异性病毒癌基因traMP，使分子 可以从癌症各个阶段的良、恶性组织中实时评估节律性 进步。此外，我们将开发表达昼夜节律报告基因的新的前列腺细胞系，因此 这种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。 这些方法一起形成了一种试验性的巡回演出，可以用来产生重要的新的 洞察昼夜节律性在前列腺癌中所起的作用，并将解决以下假设 周围结构的节律性与生物体对抗发育和死亡的能力密切相关 癌症的进展。这些实验将为未来研究通过什么机制 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.