70 KD HSPS- MODULATORS OF DEVELOPMENTAL TOXICITY

尽管已知有多种环境因子可以破坏 发展在动物和人类中，我们对可能导致癌症的因素知之甚少。 激活到。保护胚胎免受潜在的致畸作用。最近 研究已经确定了一个基因家族及其各自的蛋白质，称为 热休克蛋白，在保护细胞免受 暴露于高温和化学损伤-在此更新建议，我们概述 热休克蛋白70（Hsp 70）是一种具有保护作用的蛋白质。 小鼠胚胎的胚胎毒性/致畸作用，2）热 休克蛋白27（Hsp 27）也可以保护小鼠胚胎免受 热休克蛋白70和热休克蛋白27介导的胚胎毒性/致畸作用 它们通过调节信号转导（促分裂原激活的 蛋白激酶）途径。为了验证这些假设，我们提出了三个具体目标。在 具体目的1，我们提出制备和使用蜕皮激素诱导的Hsp 70 转基因小鼠，以确定是否诱导型Hsp 70，在足够的水平， 保护小鼠胚胎免受高温的胚胎毒性/致畸作用。 此外，我们建议使用热休克因子1（HSF 1）敲除小鼠，其中 阻断所有热诱导型Hsps的表达，以确定Hsps是否 保护植入后小鼠胚胎免受胚胎毒性 热疗的影响。在具体目标2中，我们建议制作和使用 蜕皮激素诱导的Hsp 27转基因小鼠，以确定是否诱导 足够水平的Hsp 27可以保护小鼠胚胎免受 高温的胚胎毒性/致畸作用。在具体目标3中，我们建议 使用在特定目标1和2中开发的转基因小鼠来确定是否 Hsp 70和Hsp 27通过调节信号转导发挥保护作用 途径。上述研究的预期结果将提供机理数据 这可能会导致旨在减少频率和/或 发育毒物引起的出生缺陷的严重程度。

Although a variety of environmental agents are known that can disrupt development. in animals and humans, little is known about factors that can be activated to. protect embryos from a potentially teratogenic exposure. Recent research has identified a family of genes and their respective proteins, known as heat shock proteins, that play a role in protecting cells from the toxic effects of exposure to hyperthermia and chemical insult- In this renewal proposal, we outline studies to test the following hypotheses: 1) Heat shock protein 70 (Hsp70) protects mouse embryos from the embryotoxic/teratogenic effects of hyperthermia, 2) Heat shock protein 27 (Hsp27) also protects mouse embryos from the embryotoxic/teratogenic effects of hyperthermia, and 3) Hsp70 and Hsp27 mediate their protective effects by modulating signal transduction (mitogen-activated protein kinase) pathways . To test these hypotheses we set forth 3 specific aims. In Specific Aim 1, we propose to make and use an ecdysone-inducible Hsp70 transgenic mouse to determine whether inducible Hsp70, at sufficient levels, can protect mouse embryos from the embryotoxic/teratogenic effects of hyperthermia. In addition, we propose to use the Heat Shock Factor 1 (HSF 1) null mice, in which expression of all heat-inducible Hsps is blocked, to determine whether Hsps are necessary to protect the postimplantation mouse embryos from the embryotoxic effects of hyperthermia. In Specific Aim 2, we propose to make and use an ecdysone-inducible Hsp27 transgenic mouse to determine whether inducible Hsp27, at sufficient levels, can protect mouse embryos from the embryotoxic/teratogenic effects of hyperthermia. In Specific Aim 3, we propose to use transgenic mice developed in Specific Aims 1 and 2 to determine whether Hsp70 and Hsp27 exert their protective effects by modulating signal transduction pathways. Results expected from the above studies will provide mechanistic data that could lead to intervention strategies designed to decrease the frequency and/or severity of birth defects caused by developmental toxicants.