MOLECULAR DYNAMICS OF IRON REGULATION AND FUNCTION

该项目和好时钢铁集团的长期目标是 来定义控制铁的分子和细胞相互作用 规则和功能。1）理解的机制 肠铁排出; 2）细胞内铁区室化; 3） 铁介导的基因调控; 4）细胞内铁调节蛋白 通量和5）复杂的细胞和分子反馈机制， 维持铁平衡是项目团队 预计将作出贡献。具体而言，个人目标是：1） 确定血色病的结构、加工和表达 疾病基因在体外和体内系统中，特别是在 铁挑战的背景; 2）研究铁的调控， 调节蛋白（IRP），通过关注转录后 细胞内易位的修饰和机制 细胞因子和铁刺激;和3）了解尼古丁诱导的 影响井内铁流动和通量的分子机制- 确定的铁负载的原代肝细胞培养系统。 该计划项目汇集了三个研究实验室， 宾夕法尼亚州立大学医学院，i）经过验证的课程 铁的分子生物学和遗传学研究记录 二）补充研究兴趣;三）建立 协作和公认的协同作用。具体建议， 题为“血色病基因的生物学功能” （项目1-Chelsea）;“铁调控的转录后调控” 蛋白质”（项目2-康纳）和“分子和细胞控制 铁调节蛋白的转录调节”（项目2-康纳） 和“载铁肝细胞的分子和细胞控制机制” （项目3-Isom）产生一种自然的联系， 系统之间的智力运动。该计划将 从核心获得基础支持，包括“金属分析和 分子遗传学”包含在更广泛的研究部门内 资源（比林斯利），这将进一步确保令人信服的互动 通过分享试剂和技术。预计各国 该小组将有助于了解生理 健康和疾病中铁通量和利用的基础过程 状态，如铁超载和贫血，阿尔茨海默病， 恶性肿瘤

The long-term goal of this Program Project and the Hershey Iron Group is to define the molecular and cellular interactions controlling iron regulation and function. The understanding of 1) the mechanisms of intestinal iron egress; 2) intracellular iron compartmentalization; 3) iron-mediated gene regulation; 4) intracellular iron-regulatory protein flux nd 5) the intricate cellular and molecular feedback mechanisms which maintain iron balance are all areas toward which the Program Project team is expected to contribute. Specifically, the individual aims are 1) to determine the structure, processing and expression of the hemochromatosis disease gene within the in vitro and in vivo systems and particularly in the context of iron challenge; 2) to study the regulation of the iron- regulatory proteins (IRPs) by focusing on post-transcriptional modifications and mechanisms of intracellular translocation following cytokine and iron stimulation; and 3) to understand the cytokine-induced molecular mechanisms effecting iron mobilization and flux within a well- defined, iron-loaded primary hepatocyte culture system. This Program Project draws together three research laboratories within the Pennsylvania State University College of Medicine with i) proven track records in the molecular biological and genetic studies of iron metabolism, ii) complementing research interests; iii) established collaborations and well-recognized synergy. The specific proposals, entitled "Biological function of the hemochromatosis disease gene" (Project 1-Chorney); "Post-transcriptional regulation of iron regulatory proteins" (Project 2-Conner) and "Molecular and cellular control transcriptional regulation of iron regulatory proteins" (Project 2-Conner) and "Molecular and cellular control mechanisms in iron-loaded hepatocytes" (Project 3-Isom) engender a natural connectedness which will facilitate the intellectual movement between systems. The Program Project will receive foundation support from a Core encompassing "Metal Analysis and Molecular Genetics" contained within the broader Division of Research Resources (Billingsley) which will further ensure cogent interactions through the sharing of reagents and technologies. It is anticipated that the group will contribute much to the understanding of the physiological processes underlying iron flux and utilization in both health and disease states such as iron overload and anemia, Alzheimer's disease and malignancy.