70 KD HSPS- MODULATORS OF DEVELOPMENTAL TOXICITY

点击翻译按钮获取中文摘要

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.