Nutritional manipulation of circadian rhythms and cancer

描述(由申请人提供)：昼夜节律性为许多分子、细胞和生物体功能提供了一个至关重要的时间框架。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--产生的。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。最近的一些报告表明，对宿主昼夜节律的实验性操纵会影响患有癌症的啮齿动物的肿瘤生长和死亡率。在人类中，有迹象表明，昼夜节律的改变与癌症风险和确诊患者的生存统计相关。因此，宿主细胞和肿瘤细胞的昼夜节律在癌症发生发展中的作用引起了人们极大的兴趣。限制喂食时间表同步行为、生理和消化器官中的基因表达的昼夜节律，也被证明抑制了格拉斯哥骨肉瘤的生长，并减缓了小鼠的相关死亡。因此，我们提出了一个项目，以更好地了解限制喂养时间表对肝脏肿瘤的预防和发展以及肿瘤节律性的影响。我们将开发一个新的模型来研究分子昼夜节律在肝细胞癌(HCC)个体发生和进展中的作用。携带报告基因PER1-荧光素酶的大鼠将接受二乙基亚硝胺(DENA)治疗。然后，我们将把这些老鼠暴露在白天、夜间或非昼夜限制的进食时间表中。肿瘤的发展将通过小口径核磁共振和死亡率每月评估一次。同时，我们将评估每种营养操作对健康肝脏和肝脏肿瘤中时钟基因表达模式的影响。这些研究将检验这一假说，即外周结构的节律性与生物体对抗癌症发展和进展的能力密切相关。这些实验将为未来研究昼夜节律和营养对这种癌症和其他癌症发展的影响奠定基础。

DESCRIPTION (provided by applicant): 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 of cancer is of great interest. Restricted feeding schedules synchronize circadian rhythms in behavior, physiology and gene expression in digestive organs was 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 prevention and development and tumor rhythmicity in liver. We will develop a new model to study the role of molecular circadian rhythms in the ontogeny and progression of hepatocellular carcinoma (HCC). Rats bearing the reporter gene Per1-luciferase will be administered Diethylnitrosamine (DENA). We will then expose these rats to daytime, nighttime, or non-circadian restricted feeding schedules. Tumor development will be assessed once per month by small-bore MRI and by mortality. In parallel we will assess the effects of each nutritional manipulation on clock gene expression patterns in healthy liver and in liver tumors. These studies will test 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 circadian and nutritional influences on development of this and other cancers.