THE CELLULAR RESPONSE TO NON-MUTAGENIC CARCINOGENS

描述：（改编自申请人摘要）：慢性低水平 暴露于环境毒素对人类健康的影响， 可能被视为正常衰老相关的发展 疾病异常折叠的蛋白质，内源性蛋白毒素，最近 已被证明有助于显着的退行性疾病，影响 中枢和外周神经系统、肝脏、内分泌腺和其他 机关环境毒素具有改变蛋白质结构的潜力 直接或间接，因此假设蛋白毒性 有助于许多环境引起的疾病的发病机制， 帕金森氏病、运动神经元病和癌症。该计划的目标 是确定环境诱导蛋白质变化的方式 结构被识别，以理解这种应力信号是如何被转换的 具体的反应，并将这些反应的背景下， physiology.这些研究将从两个方面对环境健康产生影响： 首先，揭示细胞适应的细节， 环境诱导的蛋白质毒性将确定反应的各个方面 其可以被修改以用于治疗目的。第二，减少环境污染 诱导蛋白质毒性，其基本分子组分（在很大程度上相同 因为某些类别的诱变剂已被简化为定义的相互作用 与DNA和染色质），这些研究将提供精确的工具， 识别新的环境危害。在实验上，重点将放在 亚砷酸盐是一种典型的毒素， 通过改变蛋白质结构的影响。信号通路连接着 砷暴露于eIF 2a磷酸化的早期事件将被定义 并且，利用小鼠中的靶向突变的能力， 将从功能上定义干扰这一途径。磷酸化 eIF 2a是一个上游信号，控制胁迫诱导的基因表达。 由这一途径控制的基因的补充将被揭示，使用一个 生物信息学和功能基因组学的结合。最后一个目的是使用 基因筛选的力量，以确定早期事件的信号通路， 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。对这些早期步骤的识别可能会提供分子生物学证据。 关于环境中最接近的大分子目标的性质的线索 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.