HYPERTHERMIA, HEAT-SHOCK RESPONSE, AND BIRTH DEFECTS

体温过高是动物中众所周知的致畸原， 人类的致畸剂除了致畸作用外，急性 高热还诱导热休克反应，其特征在于 转录和翻译的改变以及热量的合成 休克蛋白（hsps）。此外，多种致畸剂能够 引发这种热休克，或者更准确地说，应激反应。 我们漫长 因此，范围目标是确定致畸原之间的关系， 诱发应激反应和诱发出生缺陷。 之一 该建议的具体目的是使用高分辨率二维 凝胶电泳结合计算机辅助图像分析， 检查的假设，诱导的压力反应，在 哺乳动物胚胎在器官发生的关键时期可以改变 遗传位点激活和失活的既定程序 正常发展必不可少。 轻度高温也可以诱导耐热状态， 细胞或胚胎的毒性作用的热量和其他应激诱导 剂.虽然其耐热机制尚不清楚， 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）已被 牵连 因此，第二个具体目标是使用抗体， cDNA，酶测定，酶抑制剂和诱导剂来检查 假设特异性热休克蛋白和/或抗氧化防御在 啮齿动物胚胎耐热性的诱导。最后我们将 构建转基因小鼠，其中特异性hsps组成型地 在β-肌动蛋白启动子的控制下表达，以测试 HSPs在诱导 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.