Selenoprotein P function and regulation of expression

描述（由申请人提供）：大量信息表明，在神经元损伤和神经退行性疾病中，活性氧和重金属毒性会造成累积细胞损伤。细胞已经进化出各种内源性抗氧化防御，以提供保护免受氧化损伤或减少氧化应激。硒是这些防御的重要贡献者，因为它是保护细胞免受正常氧代谢的破坏性产物的抗氧化酶家族的活性所必需的。长期以来，硒也被认为是重金属毒性的解毒剂。硒蛋白P最近已被证明作为硒递送蛋白到大脑，当饮食中硒缺乏时，为合成其他硒蛋白提供这种必需微量元素的来源。靶向破坏硒蛋白P基因导致神经功能障碍。本研究的总体目标是研究硒蛋白P在神经元来源的细胞中的硒传递功能，并确定关键的靶硒蛋白，其功能是保护氧化剂和重金属诱导的损伤，并可能解释硒蛋白P基因中断的神经效应。将通过以下具体目标实现这些目标： 1.研究硒蛋白P作为培养细胞的硒供体的方法，包括细胞膜和细胞内的相互作用。 2.研究特定硒蛋白的表达水平和亚细胞定位，以及定位或表达水平或模式是否会因氧化损伤而改变。研究小鼠不同脑区组织切片中特异性硒蛋白的表达，以及GSH耗竭或缺血/再灌注损伤后表达水平或定位的变化。 3.鉴定神经元细胞中负责保护免受氧化损伤的特定硒蛋白，氧化损伤由活性氧产生或积累或重金属诱导的损伤引起。 4.研究在尸检时获得的一组日本男性脑切片中硒蛋白的表达，这些男性被诊断患有阿尔茨海默病或帕金森病，血管性痴呆，其他神经损伤或没有神经退行性疾病的证据。

DESCRIPTION (provided by applicant): There is a wealth of information implicating cumulative cellular injury inflicted by reactive oxygen species and heavy metal toxicity in neuronal damage and neurodegenerative diseases. Cells have evolved various endogenous antioxidant defenses to afford protection from oxidative injury or to reduce oxidative stress. Selenium is an essential contributor to these defenses, as it is required for the activity of a family of antioxidant enzymes that protect cells against the damaging products of normal oxygen metabolism. Selenium has also long been known to function as an antidote to toxicity of heavy metals. Selenoprotein P has recently been shown to function as a selenium delivery protein to brain, providing a source of this essential trace element for synthesis of other selenoproteins when selenium is deficient in the diet. Targeted disruption of the selenoprotein P gene results in neurological dysfunction. The overall goals of this study are to investigate the selenium delivery function of selenoprotein P in cells of neuronal origin, and to identify the crucial target selenoproteins which function in protection from oxidant and heavy metal induced damage, and which presumably explain the neurological effects of selenoprotein P gene disruption. These goals will be addressed through the following specific aims: 1. Investigate the means by which selenoprotein P serves as a Se donor to cells in culture, including interactions at the cell membrane and within the cell. 2. Investigate the expression levels and subcellular localization of specific selenoproteins, and whether localization or expression levels or patterns change in response to oxidative damage. Investigate the expression of specific selenoproteins in tissue sections from different brain regions in mice, and the changes in the expression levels or localization in response to GSH depletion or ischemia/reperfusion injury. 3. Identify the specific selenoproteins in neuronal cells responsible for protection from oxidative damage, resulting from either reactive oxygen species production or accumulation, or heavy metal induced damage. 4. Investigate expression of selenoproteins in brain sections obtained at autopsy from a cohort of Japanese men diagnosed with Alzheimer's or Parkinson's disease, vascular dementia, other neurological damage or with no evidence of neurodegenerative disease.