Ferritin, Iron Homeostasis and Cellular Stress

描述(申请人提供)：金属化学和分子生物学 在铁蛋白的结构和功能的研究中汇聚在一起。铁蛋白是 一种铁结合蛋白，其调节曾被认为只对 细胞铁含量的变化，最近被证明是有针对性的 通过应激诱导的刺激，包括细胞因子、氧化剂和一系列 外源生物。我们现在知道，像肿瘤坏死因子，反应性 氧物种和其他刺激触发铁蛋白诱导；铁蛋白，在 反过来，通过隔离反应性低分子来改变细胞铁的动态平衡 重量“细胞铁。这反过来又降低了对 压力。在这个提案中，我们探索了铁蛋白调节是 有助于调节细胞反应的大小和特征 伤害和压力。我们研究了铁蛋白对 暴露于促氧化剂和抗氧化剂的细胞和组织的表型。在我们的 第一个特定的目标，我们探索铁蛋白的分子机制 参与化学预防对促氧化剂外源生物的反应。在我们的 第二个特定目标，我们探索氧化应激的潜在途径 调节健康和疾病中的铁蛋白。在我们的第三个具体目标中，我们发展 在活体小鼠模型中测试我们的发现在 整只动物。

DESCRIPTION (provided by applicant): The metallochemistry and molecular biology of iron converge in the study of ferritin structure and function. Ferritin is an iron binding protein whose regulation, once thought to be responsive only to changes in cellular iron content, has more recently been shown to be targeted by stress-induced stimuli, including cytokines, oxidants, and a range of xenobiotics. We now know that agents such as tumor necrosis factor, reactive oxygen species, and other stimuli trigger ferritin induction; ferritin, in turn, alters cellular iron homeostasis by sequestering reactive, "low molecular weight" cellular iron. This in turn reduces susceptibility to subsequent stress. In this proposal we explore the hypothesis that ferritin regulation is instrumental in modulating the magnitude and character of the cellular response to injury and stress. We examine the unique contribution of ferritin to the phenotype of cells and tissues exposed to prooxidants and antioxidants. In our first Specific Aim, we explore the molecular mechanisms by which ferritin participates in the chemopreventive response to prooxidant xenobiotics. In our second Specific Aim, we explore potential pathways by which oxidative stress regulates ferritin in health and disease. In our third Specific Aim, we develop in vivo mouse models to test the relevance of our findings in the context of whole animals.