HYPERTHERMIA, HEAT SHOCK RESPONSE, AND BIRTH DEFECTS

体温过高是一种众所周知的动物， 很有可能是人类致畸物质，主要产生 中枢神经系统畸形。除了它的 致畸作用，急性体温过高已被证明可导致 在各种细胞中所谓的热休克反应 从细菌到人类的有机体。热冲击反应是 以转录和翻译方面的变化为特征的 几种热休克蛋白的合成。近期 研究证明，除了体温过高外，还有一种 各种其他物理和化学试剂，其中许多是 也就是致畸物质，能够引起所谓的 应激反应，体温过高是最好的研究例子。 拟议中的研究的长期目标过于确定 无论应激反应，其特征是改变 转录和最终合成特定应力 蛋白质，在致畸过程中起作用 体温过高和其他致畸因素。 这项提案的具体目标集中在以下几个方面 应激反应与应激诱导的关系 哺乳动物(大鼠)胚胎发育异常。初步 我们实验室的结果表明，高温诱导的 发育异常与八项指标的诱导有关 热休克蛋白的一个特定目标是表征 利用这些技术进一步研究大鼠胚胎的热休克反应 体外培养、放射性同位素标记和二维凝胶 电泳法。第二个具体目标是检查 假设应激反应，即改变转录 和/或热休克蛋白，构成了 畸形症。这一假设将使用多方面的 方法包括：1/a直接评估是否 转录的发育程序因受热而改变，2/ 发展阶段之间是否存在相关性， 热休克蛋白的诱导和发育异常，3/a遗传 热致脑外畸形和热休克综合征的敏感性分析，4/ 抑制剂对热休克蛋白合成的调控及5/是否有其他作用 已知的致畸物质会引起热休克反应。基于 最近的证据表明，特定的应激蛋白可能在 在提供保护免受特定应力影响方面的作用 蛋白质可能在提供保护作用方面发挥作用。 对于体温过高，第三个具体目标是确定 特定应激蛋白在保护胚胎免受 热和其他致畸物质的致畸作用。

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.