HYPERTHERMIA, HEAT-SHOCK RESPONSE, AND BIRTH DEFECTS

体温过高是动物的一种众所周知的致畸因素，可能是 人类体内的致畸物质。除了它的致畸作用外，急性 体温过高还会引起热休克反应，其特征是 转录和翻译的变化与热的合成 休克蛋白(HSPs)。此外，各种致畸物质都能够 引发这种热休克，或者更确切地说，是应激反应。我们的龙 因此，Range的目标是定义致畸因素-- 诱导应激反应和出生缺陷的诱导。其中一个 这项提议的具体目的是使用高分辨率的二维 凝胶电泳与计算机辅助图像分析相结合 检验这样一种假设，即应激反应的诱导 哺乳动物胚胎在器官发生的关键时期可以改变 建立遗传基因座的激活和失活程序 对正常发育来说是必不可少的。 轻度高热也可以诱导一种耐热状态，以保护 细胞或胚胎免受高温和其他应激诱导的毒性效应 探员们。尽管耐热性的机制还不是很好 了解特定的热休克蛋白(热休克蛋白27和72)和抗氧化防御 (谷胱甘肽、超氧化物歧化酶和谷胱甘肽过氧化物酶) 牵连其中。因此，第二个特定目标是使用抗体， CDNA、酶分析、酶抑制剂和诱导剂来检测 假设特定的热休克蛋白和/或抗氧化防御在 啮齿动物胚胎耐热性的诱导。最后，我们会 构建结构性表达特定热休克蛋白的转基因小鼠 在β-肌动蛋白启动子控制下表达，以测试 假设热休克蛋白在诱发糖尿病的过程中起直接作用 啮齿动物胚胎的耐热性。

Hyperthermia is a well known teratogen in animals and a suspected teratogen in humans. In addition to its teratogenic effects, acute hyperthermia also induces a heat shock response characterized by alterations in transcription and translation and the synthesis of heat shock proteins (hsps). Furthermore, a variety of teratogens are capable of inducing this heat shock, or more properly, stress response. Our long range goal, therefore, is to define the relationship between teratogen- induced stress response and the induction of birth defects. One of the specific aims of this proposal is to use high resolution two-dimensional gel electrophoresis coupled with computer-assisted image analysis to examine the hypothesis that the induction of a stress response in the mammalian embryo during the critical period of organogenesis can alter the established program of activation and inactivation of genetic loci essential for normal development. Mild hyperthermia can also induce a thermotolerant state that protects cells or embryos from the toxic effects of heat and other stress-inducing agents. Although the mechanisms underlying thermotolerance are not well understood, specific hsps (hsp 27 and 72) and antioxidant defenses (glutathione, superoxide dismutase and glutathione peroxidase) have been implicated. A second specific aim, therefore, is to use antibodies, cDNAs, enzyme assays, enzyme inhibitors and inducers to examine the hypothesis that specific hsps and/or antioxidant defenses play a role in the induction of thermotolerance in rodent embryos. Finally, we will construct transgenic mice in which specific hsps are constitutively expressed under the control of a beta-actin promoter to test the hypothesis that hsps play a direct role in the induction of thermotolerance in rodent embryos.