THE CELLULAR RESPONSE TO NON-MUTAGENIC CARCINOGENS

描述：(改编自申请者摘要)：慢性低水平 暴露于环境毒素对人类健康的影响 在其他情况下可能被视为正常衰老相关疾病的发展 疾病。异常折叠的蛋白质，内源性蛋白毒素，最近 已被证明对影响 中枢和外周神经系统、肝脏、内分泌腺等 器官。环境毒素有可能改变蛋白质结构 直接或间接的，因此蛋白质毒性被假设为 与许多环境引起的疾病的发病机制有关 帕金森氏病、运动神经元疾病和癌症。这个项目的目标是 是定义环境引起的蛋白质变化的方式 结构识别，以了解这种应力信号是如何传递的 并将这些反应放在细胞的背景下 生理学。这些研究将从两个方面影响环境健康： 首先，揭示了细胞适应的细节 环境诱导的蛋白毒性将确定反应的各个方面 这可能会被修改以达到治疗目的。第二，通过减少环境污染 对其基本分子成分的诱导蛋白毒性(大致相同 随着某些类别的诱变剂被减少到定义的相互作用 DNA和染色质)，这些研究将为 识别新的环境危害。在实验中，重点将放在 对亚砷酸盐的应激反应，一种被认为能发挥其许多作用的典型毒素 通过改变蛋白质结构来发挥作用。连接在一起的信号通路 亚砷酸盐暴露于eIF2a磷酸化的早期事件将被定义 而且，利用小鼠体内定向突变的力量，其后果是 干扰这一途径的可能性将被从功能上定义。磷酸化 EIF2a是一个上游信号，控制应激诱导的基因表达。 由这条途径控制的基因的补体将被揭示，使用 生物信息学和功能基因组学的结合。最后一个目标是使用 基因筛选的力量定义信号通路中的早期事件， 特异性地响应亚砷酸盐并激活一种新的亚砷酸盐诱导基因， Airap/AIP-1。对这些早期步骤的鉴定可能会为 关于环境分子近端大分子靶标性质的线索 蛋白毒性。

DESCRIPTION: (Adapted from the Applicant's Abstract): Chronic low level exposure to environmental toxins impacts on human health by promoting the development of what might otherwise be regarded as normal aging related diseases. Abnormally folded proteins, endogenous proteotoxins, have recently been shown to contribute significantly to degenerative diseases affecting the central and peripheral nervous system, liver, endocrine glands and other organs. Environmental toxins have the potential to modify protein structure directly or indirectly and therefore proteotoxicity is hypothesized to contribute to pathogenesis of many environmentally induced disorders such as Parkinson's disease, Motor Neuron Disease and Cancer. The goal of this program is to define the manner by which environmentally induced changes in protein structure are recognized, to understand how such stress signals are transduced to specific responses and to place these responses in the context of cellular physiology. These studies will impact on environmental health in two ways: First, revealing the details of the cellular adaptation to environmentally-induced proteotoxicity will identify aspects of the response that may be modified to therapeutic ends. Second, by reducing environmentally induced proteotoxicity to its essential molecular components (in much the same way as certain classes of mutagens have been reduced to defined interactions with DNA and chromatin), these studies will provide precise tools for identifying new environmental hazards. Experimentally, the focus will be on stress responses to arsenite, a prototypical toxin thought to exert many of its effects by modifying protein structure. The signaling pathways that link arsenite exposure to the early event of eIF2a phosphorylation will be defined and, utilizing the power of targeted mutagenesis in the mouse, the consequences of interfering with this pathway will be defined functionally. Phosphorylation of eIF2a is an upstream signal that controls stress-induced gene expression. The complement of genes controlled by this pathway will be revealed, using a combination of bioinformatics and functional genomics. The last aim is to use the power of genetic screens to define early events in a signaling pathway that specifically responds to arsenite and activates a novel arsenite-induced gene, Airap/aip- 1. Identification of these early steps will likely provide molecular clues as to the nature of the proximal macromolecular targets of environmental proteotoxicity.