The Impact of Anthrax Toxin on Embryonic Development

描述（由申请人提供）：炭疽芽孢杆菌致死毒素和水肿毒素分别通过破坏MAPKK信号通路和引起cAMP积累来改变细胞生理。MAPKK信号和cAMP都是发育的重要调节因子，胚胎暴露于炭疽毒素可能导致缺陷。在最近的DNA阵列研究中，我们发现Wnt信号也可能被致命毒素破坏。Wnt信号是发育的重要组成部分，该通路的异常也可能导致胚胎发育中的缺陷。根据这些观察，我们对斑马鱼胚胎进行了初步实验，发现用炭疽毒素处理后存在明显缺陷。这些结果强烈表明，需要更好地了解炭疽毒素对发展的影响。如果一名生物恐怖分子在人口密集地区传播炭疽芽孢杆菌，那么至少1.5%的人口将怀孕，胚胎可能会接触到这种毒素。因此，为了更好地了解炭疽毒素对胚胎发育的影响，我们将解决两个具体目标。具体目标我们将确定致死毒素和水肿毒素对斑马鱼胚胎发育的影响。具体目标2。我们将确定失活炭疽毒素突变体对斑马鱼胚胎发育的影响。具体目标2将解决疫苗和候选治疗可能导致发育缺陷的可能性。

DESCRIPTION (provided by applicant): Bacillus anthracis lethal toxin and edema toxin modify the physiology of cells by disrupting MAPKK signaling pathways and causing accumulation of cAMP respectively. Both MAPKK signaling and cAMP are important regulators of development and exposure of embryos to anthrax toxin could lead to defects. In recent DNA array studies we have found that Wnt signalling may also be disrupted by lethal toxin. Wnt signaling is a major part of development and aberrations in this pathway could also lead to defects in the developing embryo. In light of these observations we carried out pilot experiments on zebrafish embryos and found noticeable defects after treatment with anthrax toxin. These results strongly suggest a better understanding of anthrax toxin's impact on development is needed. In the case of a bioterrorist disseminating B. anthracis spores over a populated area, at least 1.5% of the human population will be pregnant and embryos could be exposed to the toxin. Therefore, in order to better understand the impact of anthrax toxin on embryonic development, we will address two specific aims. Specific Aim 1. We will determine the impact lethal toxin and edema toxin have on zebrafish embryo development. Specific Aim 2. We will determine the impact inactive anthrax toxin mutants have on zebrafish embryo development. Specific aim 2 will address the possibility that vaccine and therapeutic candidates might cause developmental defects.