Trace element dynamics in the vertebrate eye

描述(申请人提供)：白内障是一种重要的健康和 全球经济问题。氧化损伤被认为是一种主要的 白内障形成的致病因素。而铁(Fe)催化自由基 反应是几乎所有氧化组织损伤的罪魁祸首，几乎没有 关于铁的代谢、储存和利用的信息在 镜头。铁以非反应形式储存在铁蛋白中，防止氧化 损坏。铁蛋白是由晶状体和导致失调的突变产生的 铁蛋白亚基的合成导致早期双眼白内障 人类。 这一建议的最重要的假设是晶状体对铁的摄取 上皮细胞及其在细胞质池和 在正常生理条件下，仔细控制存储和使用 条件。提高低分子铁含量的因素 重量较大的细胞质池会增加对氧化应激的易感性 紫外线照射，而缩小这个池的大小是保护的。 这项提议的第一个具体目标是确定细胞内Fe 动力学，包括铁的吸收和外流，合成和浓缩 铁蛋白、铁在铁蛋白中的储存和低分子铁的含量 细胞质库的重量受环境因素的影响而变化 铁蛋白亚基组成。第二个具体目标是确定是否 晶状体上皮细胞内正常铁分布的紊乱导致 改变细胞代谢，影响其抵御氧化的能力 应激或紫外线照射。 这些研究的结果将为我们的 对铁的代谢和安全储存的了解 具有破坏性的氧化反应。这样的信息可能会导致 用于延缓或预防白内障的有效治疗干预措施 进步。

DESCRIPTION (provided by applicant): Cataract is a significant health and economic problem worldwide. Oxidative damage has been implicated as a major causative factor in cataract formation. While iron (Fe) catalyzed free radical reactions are responsible for virtually all oxidative tissue damage, little information is available concerning Fe metabolism, storage and utilization in the lens. Storage of Fe in a non-reactive form in ferritin, prevents oxidative damage. Ferritin is made by the lens and a mutation resulting in dysregulation of the synthesis of ferritin subunits results in early bilateral cataracts in humans. The overlying Hypothesis of this proposal is that the uptake of Fe by lens epithelial cells and its movement between a cytoplasmic pool and sites of storage and utilization are carefully controlled under normal physiological conditions. Factors which increase the concentration of Fe in a low molecular weight cytoplasmic pool cause increased susceptibility to oxidative stress and UV irradiation, while a decrease in the size of this pool is protective. The first specific aim of this proposal is to determine how intracellular Fe dynamics, including Fe uptake and efflux, synthesis and concentration of ferritin, storage of Fe in ferritin and the amount of Fe in a low molecular weight cytoplasmic pool are altered by environmental factors and changes in ferritin subunit composition. The second specific aim is to determine whether disturbances in normal Fe distribution within lens epithelial cells result in altered cellular metabolism and affect their ability to withstand oxidative stress or UV irradiation. The results of these studies will provide information essential to our understanding of the metabolism and safe storage of Fe, the central component of damaging oxidative reactions. Such information could lead to the development of effective therapeutic interventions for the delay or prevention of cataract progression.