MEMBRANE COMPOSITION AND HYPERTHERMIC CELL DEATH

膜成分和高温细胞死亡

• 批准号: 3166602
• 负责人: MILTON B YATVIN
• 金额: $ 20.28万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-06-05 至 1991-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3166602
• 关键词: Escherichia coli; biophysics; cell death; cytotoxicity; fluorescent dye /probe; gamma radiation; intracellular; lipid structure; local anesthetics; membrane lipids; membrane structure; optical polarization; procainamide; propranolol; radiation sensitivity; radiopharmacology; unsaturated fatty acids

These studies are predicated on the hypothesis that the cellular membrane, specifically the organizational integrity of the membrane lipids, is the initial target of hyperthermia. The continuing goals of these studies are to delineate the direct or indirect response subsequent to the membrane insult which leads to cell death, to differentiate the mechanisms responsible for heat and irradiation killing and to develop protocols which enhance thermosensitivity. One test of the hypothesis is to examine the thermosensitivity of cells and tissues grown under protocols which modify in a systematic manner the lipid constituents of their membranes. The thermal and irradiation sensitivities of a series of organisms progressing in biological complexity from a fatty acid auxotroph of E. coli, K1060 to an in vivo solid tumor, the CA755 mammary adenocarcinoma transplanted to a BDF1, mouse will be studied. One protocol which varies the fatty acid supplement of the medium for the L1060 system exerts near absolute control on the biochemical make up and biophysical characteristics of the cell membrane. Another protocol utilizes variation in dietary linoleate initiate adaptive responses for the solid tumor model which tend to maintain host tissue membrane and to a lesser extent tumor membrane properties for optimal function. In this system there are protocols (e.g., local and systemic anesthetics, cholesterol inhibitors) which interfere with the diet-mediated adaptive responses in membrane composition. Falling between these extremes in biological complexity are two models, the E. coli B/r and Bs-1 and V79 and P388 mammalian cells. Each protocol includes the exhaustive analysis of membrane constitutents (phospholipid species, relative proportion, concentrations, and fatty acid patterns; protein concentration and two dimensional PAGE patterns, and when appropriate cholesterol concentration, lipopolysaccharide concentration, fatty acid pattern and microviscosity), the results of which will be examined in relation to shifts in the organisms thermal sensitivity. These models provide a means for comparing the mechanisms of hyperthermia-induced membrane-initiated cell killing and killing by irradiation. These studies of adaptive thermotolerance and hyperthermic lethality are intended to answer questions relevant to the design of clinical studies using hyperthermia.

这些研究是基于这样的假设：细胞膜， 特别是膜脂的组织完整性，是 体温过高的初始目标。这些研究的持续目标是 描绘膜后的直接或间接反应 导致细胞死亡的侮辱，以区分机制 负责热和辐射杀灭，并制定方案， 增强热敏性。对这一假设的一种检验是检验 在修改协议下生长的细胞和组织的热敏感性 以一种系统的方式检测它们的膜中的脂质成分。这个 一系列生物进化过程中的热和辐射敏感性 在来自大肠杆菌脂肪酸营养缺陷体的生物学复杂性中，K1060到 CA755乳腺癌移植瘤的体内实体瘤 BDF1、小鼠为研究对象。一种改变脂肪酸的方案 对L1060系统进行近乎绝对控制的介质补充 论细胞的生化组成和生物物理特性 薄膜。另一种方案是利用饮食中亚油酸的变化 启动实体肿瘤模型的适应性反应，这往往会 维持宿主组织膜和较小程度的肿瘤膜 最优函数的性质。在该系统中存在协议(例如， 局麻药和全身麻醉剂、胆固醇抑制剂) 在膜成分中具有饮食介导的适应性反应。坠落 在生物学复杂性的这两个极端之间是两种模型，即大肠杆菌 B/R和BS-1、V79和P388哺乳动物细胞。每个协议都包括 膜成分的详尽分析(磷脂物种， 相对比例、浓度和脂肪酸模式；蛋白质 集中度和二维页面模式，并在适当的时候 胆固醇浓度、脂多糖浓度、脂肪酸 模式和微粘度)，其结果将在 与生物体热敏感度的变化有关。这些型号 提供了一种比较高热诱导的机制的手段 膜启动的细胞杀伤和辐射杀伤。这些研究 适应性耐热性和高温致死性的目的是 回答与临床研究设计相关的问题 体温过高。