Oxidant induced gene expression in vitamin E deficient *

描述（由申请人提供） 这项研究的长期目标是确定分子机制 膳食抗氧化剂与细胞和 环境氧化剂在体内的应用全球基因表达 分析. 选择性缺失的转基因小鼠的可用性 α-生育酚（α-TC）转移蛋白基因，以及由此产生的耗竭 组织a-TC（维生素E），提供了一个独特的机会，严格检查 生物膜的主要膳食抗氧化剂的作用， 脂蛋白在正常生理中的作用。 此外，它作为一个 膳食补充剂干预慢性病的发病机制 由氧化剂引发的环境中的污染物也可以进行测试。 的 该建议的具体目标是：（1）定义和比较mRNA a-生育酚转移蛋白在肺和肝中的表达谱 TTP-KO和野生型小鼠;（2）检测mRNA表达的变化 肺和肝对光化学产生的 环境氧化剂，臭氧，在TTP-KO和野生型小鼠;和（3）评估 由选定的mRNA编码的蛋白质表达的变化， 通过特定目标1和2识别，通过免疫印迹和免疫- 组织化学分析 这项研究将首次确定基因组反应， 在体内沉默的基因，其产品发挥重要作用， 膜脂蛋白中主要抗氧化剂的体内平衡。 此外，本发明还提供了一种方法， 全球基因表达分析也将确定a- TC可能与清除活性氧无直接关系 种属和TTP耗竭的分子反应与 a-TC的转移。 基因表达分析暴露于 环境氧化剂臭氧，其主要目标是膜环境， 将确定体内对氧化应激的“转录”反应， 受到环境污染物和膳食抗氧化剂的作用， 维生素E对氧化剂诱导的靶基因表达变化的影响 组织中 对选定的mRNA编码的蛋白质的分析将建立 检测到的mRNA变化的潜在功能影响， 基因阵列分析。 这些分子数据可能为 设计更有效的抗氧化剂饮食干预方案 可能改善由环境氧化剂引起的肺部疾病。

DESCRIPTION (provided by applicant) The long-term objectives of this research are to define molecular mechanisms underlying interactions of dietary antioxidants with cellular and environmental oxidants in vivo by the application of global gene expression analysis. The availability of transgenic mice with selective deletion of the gene for alpha-tocopherol (a-TC) transfer protein, and the resulting depletion of tissue a-TC (vitamin E), offers a unique opportunity to rigorously examine the role of a major dietary antioxidant of biological membranes and lipoproteins in normal physiology. In addition, its potential role as a dietary supplement to intervene in the pathogenesis of chronic diseases triggered by oxidant pollutants in the environment can also be tested. The specific aims of this proposal are to: (1) define and compare the mRNA expression profiles of lungs and livers from a-tocopherol transfer protein knockout (TTP-KO) and wild type mice; (2) assay the changes in mRNA expression profiles of lungs and livers in response to a photochemically-generated environmental oxidant, ozone, in TTP-KO and wild type mice; and (3) evaluate the changes in the expression of proteins encoded by selected mRNAs, identified through specific aims 1 and 2, by immunoblot and immuno- histochemical analysis. The proposed research will identify, for the first time, the genomic response in vivo to silencing of a gene whose product plays a significant role in the homeostasis of a primary antioxidant in membranes lipoproteins. In addition, global gene expression analysis will also identify the molecular targets of a- TC that may not be directly related to the scavenging of reactive oxygen species and the molecular response to depletion of TTP not directly related to the transfer of a-TC. Gene expression analysis following exposure to an environmental oxidant, ozone, whose primary target is the membrane milieu, will identify the "transcriptional" response in vivo to oxidative stress inflicted by an environmental pollutant and the role of a dietary antioxidant, vitamin E, on oxidant-induced changes in gene expression in the target tissues. The analysis of proteins encoded by selected mRNAs will establish the potential functional implications of changes in the mRNAs detected by analysis with gene arrays. These molecular data may provide the basis for designing more effective protocols for dietary interventions with antioxidants that might ameliorate lung diseases induced by environmental oxidants.