ELF Electromagnetic Fields and Cancer

ELF电磁场与癌症

• 批准号: 6623772
• 负责人: HOWARD R PETTY
• 金额: $ 23.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-17 至 2005-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623772
• 关键词: DNA damage; NAD(H) phosphate; biological signal transduction; biophysics; calcium channel; calcium flux; cell biology; cell morphology; electromagnetic radiation; electrophysiology; environment related neoplasm /cancer; gene targeting; genetically modified animals; glucose transport; human tissue; ion channel blocker; laboratory mouse; leukocytes; microscopy; neoplastic cell; oxidative stress; potassium channel; radiation related neoplasm /cancer; radiobiology; tissue /cell culture

The interactions of electric fields with living cells is an important problem in both basic research and clinical science. Although the mechanism of intermediate strength electric field- to-cell interactions been described, the mechanism of weak field- to-cell interaction is not understood. The inability to sort out a mechanism may be due to a failure to properly isolate the inherent variables, not the lack of an effect. During the first two years of this program we have identified amplitude modulation of NAD(P)H oscillations (or metabolic resonance) as a robust experimental tool to detect weak field interactions with cells then linked it to a broad spectrum of physiological changes in cells (oxidant production, extraordinary lengthening, and DNA damage). Preliminary studies indicate that membrane channels participate in detecting weak electric fields. This is likely to be the same mechanism as the intermediate strength fields, except that the timing of the field must co-incide with endogenous intracellular oscillators to permit detection. Thus, we will test the hypothesis that phase-matched DC and AC electric fields induce metabolic resonance in leukocytes and tumor cells via the transmembrane signaling apparatus. The role(s) of plasma membrane potassium and calcium channels will be examined with a panel of pharmacologic reagents in dose-response studies. The participation of calcium in coupling electric fields to metabolic resonance will be tested using several complementary approaches. We will use cells from CD38 knock-out mice, calcium pump inhibitors, and second messenger blockers of the inositol trisphosphate and cyclic-ADP-ribose systems, to test the role of the calcium signaling apparatus in metabolic resonance and DNA damage. To test theoretical predictions, we will assess the distribution of ion channels during various cellular conditions. We will also employ high-speed microscopy, developed during the first two years of this program, to directly image changes in calcium signaling during exposure to phase-matched and phase- mismatched electric fields. To determine the mechanism linking electric fields to alterations in cell metabolism, we will also test the role of glucose transport in metabolic resonance. Thus, the molecular mechanism leading to metabolic resonance and downstream effects on superoxide release and DNA damage will be ascertained. We anticipate that these studies will broadly contribute to a fundamental understanding of how cells interpret extracellular signals. This, in turn, will identify the conditions that may permit cells to be damaged by weak extracellular electromagnetic fields. Moreover, the ability of electric fields to remotely influence cell shape and metabolism may be of broad importance in human health.

电场与活细胞的相互作用是基础研究和临床科学中的一个重要问题。尽管描述了中等强度电场与细胞相互作用的机制，但弱电场与细胞相互作用的机制尚不清楚。 无法理清机制可能是由于未能正确隔离固有变量，而不是缺乏效果。 在该项目的前两年，我们已经确定 NAD(P)H 振荡（或代谢共振）的振幅调制是一种强大的实验工具，可检测与细胞的弱场相互作用，然后将其与细胞中的广泛生理变化（氧化剂产生、异常延长和 DNA 损伤）联系起来。 初步研究表明膜通道参与弱电场的检测。 这可能是与中等强度场相同的机制，只是场的时间必须与内源性细胞内振荡器一致以允许检测。 因此，我们将测试相位匹配的直流和交流电场通过跨膜信号传导装置在白细胞和肿瘤细胞中诱导代谢共振的假设。 在剂量反应研究中，将使用一组药理学试剂来检查质膜钾和钙通道的作用。 将使用几种互补的方法来测试钙在耦合电场与代谢共振中的参与。我们将使用来自 CD38 敲除小鼠的细胞、钙泵抑制剂以及三磷酸肌醇和环 ADP-核糖系统的第二信使阻滞剂，来测试钙信号装置在代谢共振和 DNA 损伤中的作用。 为了测试理论预测，我们将评估各种细胞条件下离子通道的分布。我们还将采用在该项目的前两年开发的高速显微镜，直接对暴露于相位匹配和相位失配电场期间钙信号的变化进行成像。 为了确定电场与细胞代谢改变之间的联系机制，我们还将测试葡萄糖转运在代谢共振中的作用。 因此，将确定导致代谢共振以及对超氧化物释放和DNA损伤的下游影响的分子机制。 我们预计这些研究将广泛有助于从根本上理解细胞如何解释细胞外信号。 反过来，这将确定细胞可能被微弱的细胞外电磁场损坏的条件。 此外，电场远程影响细胞形状和新陈代谢的能力可能对人类健康具有广泛的重要性。