70 KD HSPS--MODULATORS OF DEVELOPMENTAL TOXICITY

描述：虽然各种物理和化学试剂破坏 在动物和人类的发展中，对这些因素知之甚少， 确定特定的动物或人类是否会对 潜在的发育毒性暴露。 最近的研究表明， 一个基因家族和它们各自的蛋白质，被称为70千道尔顿热量 休克蛋白（Hsp 70）家族，在保护细胞中起作用， 器官免受高温和化学品的毒性影响 侮辱。 此外，作者实验室和其他机构的研究表明， 实验室已经暗示这些热休克蛋白作为调节剂， 哺乳动物胚胎的发育毒性。 以更精确地确定 特异性热休克蛋白在发育调控中作用 毒性，提出了三个具体目标。 在具体目标1中， 建议使用过表达特异性热休克的转基因小鼠 蛋白质，以测试这一假设，即诱导型Hsp 70的过表达将 降低植入后早期小鼠胚胎对 某些发育毒物的致畸作用。 在具体目标2中， 建议使用转基因小鼠，其中Hsp 70-1和Hsp 70-3 基因已经通过同源重组失活，以测试 假设Hsp 70-1/3缺失将增加早期诊断的敏感性， 移植后小鼠胚胎的转基因效应 发育毒物 在具体目标3中，建议使用这些 功能获得和功能丧失转基因研究 Hsp 70-1/3通过与Hsp 70-1/3相互作用发挥其调节活性假说 与细胞周期机制，从而防止不适当的细胞死亡。 在这项工作中，提出的发育毒物将是体温过高， 环磷酰胺

DESCRIPTION: Although a variety of physical and chemical agents disrupt development in animals and humans, little is known about factors that determine whether a particular animal or human will be sensitive to a potentially developmentally toxic exposure. Recent research has identified a family of genes and their respective proteins, known as 70 kilodalton heat shock protein (Hsp 70) family, that plays a role in protecting cells and organs from the toxic effects of exposure to hyperthermia and chemical insult. In addition, research from the author's laboratory and other laboratories has implicated these heat shock proteins as modulators of developmental toxicity in mammalian embryos. To determine more precisely the role of specific heat shock proteins in modulating developmental toxicity, three specific aims are proposed. In specific aim 1, it is proposed to use transgenic mice that overexpress specific heat shock proteins to test the hypothesis that overexpression of inducible Hsp70 will decrease the sensitivity of early postimplantation mouse embryos to the teratogenic effects of selected developmental toxicants. In specific aim 2, it is proposed to use transgenic mice in which the Hsp 70-1 and Hsp 70-3 genes have been inactivated by homologous recombination to test the hypothesis that loss of Hsp 70-1/3 will increase the sensitivity of early postimplantation mouse embryos to the transgenic effects of selected developmental toxicants. In specific aim 3, it is proposed to use these gain-of-function and loss-of-function transgenics to investigate the hypothesis that Hsp 70-1/3 exerts its modulating activity by interacting with the cell cycle machinery, thereby preventing inappropriate cell death. In the work proposed the developmental toxicants will be hyperthermia and cyclophosphamide.