CORNEAL-EPITHELIAL NUCLEAR FERRITIN AND U.V. PROTECTION

描述：紫外线(UV)对身体所有暴露的组织，包括构成角膜和其他潜在眼睛结构的组织，构成了一种主要的环境侮辱。紫外线可以破坏包括DNA在内的多种大分子成分，例如导致癌症。这种损害可以是直接的，也可以是通过产生活性氧物种(ROS)间接造成的。然而，角膜上皮(CE)细胞似乎对这种损伤难以抵抗。这些细胞的癌症是罕见的，尽管这种组织是透明的，暴露在诱变的紫外线和其他来源的ROS下。以前的研究表明，CE细胞进化出的一种防止DNA损伤的机制涉及铁蛋白在核定位中的作用。这种分子似乎极大地减弱了紫外线产生的ROS对DNA的影响--最有可能的是通过隔离游离铁来发挥作用，后者是产生羟基自由基的催化剂，而羟基自由基是最具破坏性的ROS。其他研究表明，铁蛋白的核定位受一种核转运蛋白的影响，这种转运蛋白被称为“铁质”。铁蛋白由两个区域组成，一个区域包含核定位信号(NLS)并负责核运输，另一个区域参与与铁蛋白的结合，铁蛋白随后携带到细胞核中。铁和铁蛋白之间的这种相互作用的机制，以及随后的核运输将被进一步研究。铁素体在转运后的命运以及磷酸化是否参与调节转运也将被调查。此外，还将研究调节铁蛋白和类铁蛋白产生的机制。这些研究将包括这些分子的合成是否相互协调，以及铁蛋白的合成是否涉及一种独特的翻译调节类型，从而导致铁蛋白含量较低。如此低铁的铁蛋白在铁隔离方面可能是高效的，因此对活性ROS具有保护作用。对于铁素体的合成，研究将涉及基因中的“应激反应元件”是否对ROS做出反应。最后，将确定在CE细胞中，核铁蛋白提供的对ROS损伤的保护是否可以提供给其他类型的细胞，在这些细胞中，ROS可能具有有害影响

DESCRIPTION: Ultraviolet (UV) light constitutes a major environmental insult to all exposed tissues of the body, including those comprising the cornea and other underlying ocular structures. UV-light can damage a wide variety of macromolecular components including DNA resulting, for example, in cancer. This damage can be direct, or it can be indirect through the generation of reactive oxygen species (ROS). Corneal epithelial (CE) cells, however, seem to be refractory to such damage. Cancers of these cells are rare, even though this tissue is transparent and exposed to mutagenic UV light and other sources of ROS. Previous studies suggest that one mechanism that CE cells have evolved to prevent damage to their DNA involves ferritin in a nuclear localization. This molecule seems to greatly diminish the effects of UV-produced ROS to DNA-most likely by sequestering free iron, which acts as a catalyst in generating hydroxyl radicals, the most damaging ROS. Other studies suggest that the nuclear localization of ferritin is effected by a nuclear transporter, which is termed "ferritoid". Ferritoid is comprised of two regions, one, which contains a nuclear localization signal (NLS) and is responsible for the nuclear transport, and another, which is involved in the binding to ferritin, which ferritoid subsequently carries into the nucleus. The mechanism of this interaction between ferritoid and ferritin, and the subsequent nuclear transport will be examined further. The fate of ferritoid following transport and whether phosphorylation is involved in regulating the transport will also be investigated. The mechanisms responsible for regulating the production of ferritin and ferritoid will also be examined. The studies will include whether the synthesis of these molecules is co-ordinate with one another and whether the synthesis of ferritin involves a unique type of translational regulation, which results in a low iron ferritin. Such a low iron ferritin may be highly efficient at iron sequestration and therefore protection against active ROS. For the synthesis of ferritoid, studies will involve whether "stress response elements" in the gene respond to ROS. Lastly, it will be determined whether the protection against damage by ROS provided by nuclear ferritin in CE-cells, can be afforded to other cell types in which ROS potentially have deleterious effects