CHRONOBIOLOGY AND OCCUPATIONAL HEALTH HAZARDS

这项研究的长期目标是确定 代谢节律对体力毒性反应的影响 刺激物、工业毒素和治疗剂。在那些拥有 已经或目前正在研究的包括：辐射、百草枯、 乌拉坦、马拉硫磷、氯化汞、胰岛素、高血糖素、表皮生长 因子(EGF)、生长抑素、促肾上腺皮质激素和胃泌素。小鼠的毒性反应 小鼠对ALL的依赖已被证明是昼夜节律依赖的。此外，还有一些 上述多肽刺激RNA和DNA合成的一些 组织包括消化道(EGF、胰岛素和胃泌素)，而 其他的主要是抑制性的(胰高血糖素、生长抑素和促肾上腺皮质激素)。 所有的反应都被发现是昼夜节律依赖的。的目的是 本申请是为了继续这样的研究，但也是为了确定 如果已经获得的时间生物学发现可以用来减少 总体毒性。 所选择的模型是细胞在某些区域的增殖 肠道，也经历了显著的昼夜节律变化。能 禁食在某一昼夜阶段开始，持续一段时间的事实 36小时或更短时间会减少增殖细胞的比例，从而 用来保护肠道免受以下物质的损害：(1)物理制剂 例如影响有丝分裂纺锤体的辐射或(2)化学物质 特异性干扰DNA的试剂，如胞嘧啶阿拉伯糖苷 合成？此外，上述任何一种多肽，当给药时 在物理或化学物质之前、同时或之后 诱发性损伤保护肠道的不同区域免受损害或增强 修理？另一个目标是深入了解其作用机制。 从EGF细胞表面水平探讨EGF的作用 受体和EGF诱导肠道细胞膜蛋白磷酸化 正常成年小鼠和接受辐射治疗的小鼠。 这些研究与工业毒理学、胃肠病学、 免疫学和内分泌学。

The long term objective of this study has been to determine what role metabolic rhythms have on influencing response to toxicity from physical stimuli, industrial toxins and therapeutic agents. Among those that have been, or currently are being investigated include: irradiation, paraquat, urethane, malathion, mercuric chloride, insulin, glucagon, epidermal growth factor (EGF), somatostatin, ACTH, and gastrin. The toxicity response in mice to all has been shown to be circadian-stage dependent. Moreover, some of the above polypeptides stimulate RNA and DNA synthesis in a number of tissues including the alimentary canal (EGF, insulin and gastrin) whereas others are predominately inhibitory (glucagon, somastatin, and ACTH), again all responses have been found to be circadian-stage dependent. The aim of the present application is to continue such studies, but also, to determine if the chronobiological findings already gained can be used to reduce overall toxicity. The model chosen has been cell proliferation in certain regions of the intestinal tract, which also undergoes remarkable circadian variation. Can the fact that fasting, beginning at a certain circadian stage, for a span of 36 hours or less reduce the fraction of proliferating cells and thus be used to protect the gut from damage brought about by: (1) a physical agent such as irradiation which affects the mitotic spindle or (2) a chemical agent such as cytosine arabinoside, which specifically interfers with DNA synthesis? Morever, will any of the above mentioned peptides, when given before, simultaneously, or subsequent to either a physical or chemical induced injury protect different regions of the gut from damage or enhance repair? Another objective is to gain insight into the mechanism of action of EGF by exploring its effect at the level of the EGF cell surface receptor and EGF induced cell membrane protein phosphorylation in the gut of normal adult mice and those treated with irradiation. These studies have relevance for industrial toxicology, gastroenterology, immunology, and endocrinology.