CHRONOBIOLOGY AND OCCUPATIONAL HEALTH HAZARDS

时间生物学和职业健康危害

• 批准号: 3420081
• 负责人: LAWRENCE E SCHEVING
• 金额: $ 11.97万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1988-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3420081
• 关键词: X ray; adrenocorticotropic hormone; bioperiodicity; body temperature regulation; cell growth regulation; cell membrane; circadian rhythms; cytosine; cytotoxicity; environmental toxicology; epidermal growth factor; esophagus; gastrins; insulin; laboratory mouse; occupational hazard; phase change; phosphoproteins; radiation sensitivity; rectum /anus; somatostatin

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.

本研究的长期目标是确定 代谢节律对身体毒性反应的影响 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：辐照，百草枯， 氨基甲酸乙酯，马拉硫磷，氯化汞，胰岛素，胰高血糖素，表皮生长 EGF、生长抑素、促肾上腺皮质激素和胃泌素。 中的毒性反应 所有小鼠都表现出昼夜节律阶段依赖性。 而且一些 上述多肽中的至少一种刺激许多细胞中的RNA和DNA合成。 包括消化道在内的组织（EGF、胰岛素和胃泌素）， 其他主要是抑制性的（胰高血糖素、生长抑素和ACTH）， 已经发现所有的反应都是昼夜节律阶段依赖性的。 的目的 本申请将继续这些研究，而且确定 如果已经获得的时间生物学发现可以用来减少 整体毒性。 所选择的模型是细胞增殖在某些区域的 肠道，这也经历了显着的昼夜变化。 可以 事实上，禁食，开始于一定的昼夜节律阶段， 36小时或更短的时间减少增殖细胞的分数， 用于保护肠道免受以下因素的损害：（1）物理因素 例如影响有丝分裂纺锤体的辐射或（2）化学物质 试剂，如阿糖胞苷，其特异性干扰DNA 合成？ 此外，当给予任何上述肽时， 在物理或化学反应之前、同时或之后， 诱导的损伤保护肠道的不同区域免受损伤或增强 修理？ 另一个目标是深入了解作用机制 EGF在细胞表面的作用 受体和EGF诱导的肠细胞膜蛋白磷酸化 正常成年小鼠和接受辐射治疗的小鼠的平均寿命。 这些研究与工业毒理学，胃肠病学， 免疫学和内分泌学。