Ferritin, Iron Homeostasis and Cellular Stress

铁蛋白、铁稳态和细胞压力

• 批准号: 6779900
• 负责人: FRANK M. TORTI
• 金额: $ 34.2万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779900
• 关键词: RNase protection assay; antioxidants; cellular pathology; chemoprevention; cytokine; ferritin; gene induction /repression; gene targeting; genetic mapping; genetically modified animals; homeostasis; immunoprecipitation; iron metabolism; laboratory mouse; model design /development; molecular cloning; oxidative stress; p53 gene /protein; polymerase chain reaction; protein structure function; southern blotting; transcription factor; yeast two hybrid system

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.

描述（由申请人提供）：金属化学和分子生物学 铁的研究集中在铁蛋白结构和功能的研究上。铁蛋白是 一种铁结合蛋白，其调节一度被认为仅对 细胞铁含量的变化，最近被证明是有针对性的 由压力引起的刺激，包括细胞因子、氧化剂和一系列 异生素。我们现在知道，诸如肿瘤坏死因子、反应性 氧气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“低分子铁”来改变细胞铁稳态 重量”细胞铁。这反过来又降低了对后续的敏感性 压力。在本提案中，我们探讨了铁蛋白调节的假设 有助于调节细胞反应的幅度和特征 受伤和压力。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 第一个具体目标，我们探索铁蛋白的分子机制 参与对促氧化异生素的化学预防反应。在我们的 第二个具体目标，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，我们制定了 体内小鼠模型来测试我们的研究结果在以下情况下的相关性 整个动物。