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.
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