HYPERTHERMIA, HEAT-SHOCK RESPONSE, AND BIRTH DEFECTS

体温过高（升高的温度）是众所周知的动物， 很可能是人类的致畸剂，主要产生 中枢神经系统的畸形 除了其 致畸作用，急性高温已被证明可诱导 在各种细胞中所谓的热休克反应， 从细菌到人类的生物体。热休克反应是 以转录和翻译的改变为特征， 几种热休克蛋白（HSP）的合成。 最近 研究表明，除了热疗， 各种其他物理和化学试剂，其中许多是 也是致畸剂，能够诱导所谓的 应激反应，体温过高是研究得最好的例子。 拟议中的研究的长期目标过于确定 无论是压力反应，其特征是改变 转录并最终合成特异性应激 蛋白质，在致畸过程中发挥作用， 体温过高和其他致畸物。 本提案的具体目标侧重于以下几个方面： 应激反应与应激诱导的 哺乳动物（大鼠）胚胎发育异常。 初步 我们实验室的结果表明， 异常发育与八个 热休克蛋白，一个具体的目的是表征 进一步利用该技术研究大鼠胚胎热休克反应 体外培养，放射性同位素标记和二维凝胶 电泳 第二个具体目标是审查 假设压力反应，即，改变的转录 和/或热休克蛋白，构成了一个基本的机制， 致畸作用 这一假设将使用多方面的测试， 方法包括：1/直接评估 转录的发育程序被热改变，2/ 发展阶段之间是否存在相关性， 热休克蛋白和异常发育的诱导，3/ a遗传 对热诱导露脑畸形和热休克蛋白的敏感性分析，4/ 用抑制剂调节HSP合成和5/是否其他 已知的致畸剂诱导热休克反应。 基于 最近的证据表明，特定的应激蛋白可能发挥作用， 在提供保护免受特定压力影响方面的作用 蛋白质可能在提供保护免受影响方面发挥作用， 第三个具体目标是确定 特定的应激蛋白在保护胚胎免受 热和其他致畸剂的致畸作用。

Hyperthermia (elevated temperature) is a well known animal and quite possibly human teratogen, producing primarily malformations of the central nervous system. In addition to its teratogenic effects, acute hyperthermia has been shown to induce the so-called heat shock response in cells of a variety of organisms from bacteria to man. The heat shock response is characterized by alterations in transcription and translation and the synthesis of several heat shock proteins (HSPs). Recent research has documented that in addition to hyperthermia a variety of other physical and chemical agents, many of which are also teratogens, is capable of inducing what has come to be called the stress response, hyperthermia being the best studied example. The long-term objective of the proposed research is too determine whether the stress response, characterized by altered transcription and culminating in the synthesis of specific stress proteins, plays a role in the teratogenic process initiated by hyperthermia and other teratogens. The specific aims of this proposal focus on several aspects of the relationship between the stress response and stress-induced abnormal development in mammalian (rat) embryos. Preliminary results from our laboratory indicate that hyperthermia-induced abnormal development is correlated with the induction of eight heat shock proteins and one specific aim is to characterize further the rat embryo heat shock response using the techniques of in vitro culture, radioisotopic labeling and two-dimensional gel electrophoresis. A second specific aim is to examine the hypothesis that the stress response, i.e., altered transcription and/or heat shock proteins, constitutes a basic mechanism of teratogenesis. This hypothesis will be tested using a multifaceted approach including: 1/ a direct assessment of whether the developmental program of transcription is altered by heat, 2/ whether a correlation exists between stage of development, induction of HSPs and abnormal development, 3/ a genetic analysis of sensitivity to heat-induced exencephaly and HSPs, 4/ modulation of HSP synthesis with inhibitors and 5/ whether other known teratogens induce a heat shock response. Based upon recent evidence indicating that specific stress proteins may play a role in providing protection from the effects of specific stress proteins may play a role in providing protection from the effects of hyperthermia, a third specific aim is to determine whether specific stress proteins play a role in protecting embryos from the teratogenic effects of heat and other teratogens.