MOLECULAR DYNAMICS OF IRON REGULATION AND FUNCTION

该计划项目和好时钢铁集团的长期目标是 定义控制铁的分子和细胞相互作用 规范和功能。对1)机制的理解 肠道铁外流；2)细胞内铁区域化；3) 铁介导的基因调控；4)细胞内铁调节蛋白 通量和5)错综复杂的细胞和分子反馈机制 保持铁平衡是计划项目团队努力的方向 预计将做出贡献。具体地说，个人目标是1)到 确定血色素沉着症的结构、加工和表达 体外和体内系统内的疾病基因，特别是在 铁挑战的背景；2)研究铁的调节-- 转录后调控蛋白(IRPS) 细胞内移位的修饰及其机制 细胞因子与铁刺激；3)了解细胞因子诱导的 影响井内铁迁移和通量的分子机制- 已确定的、含铁的原代肝细胞培养体系。 该计划项目将三个研究实验室聚集在一起 宾夕法尼亚州立大学医学院，i)经过验证的赛道 铁的分子生物学和遗传学研究记录 新陈代谢，二)补充研究兴趣；三)建立 合作和公认的协同效应。具体的建议， 题为《血色素沉着病基因的生物学功能》 (项目1--Chorney)；“铁的转录后调控 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控“(项目2--康纳) 和“铁负载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，这将促进 系统之间的智力运动。该计划项目将 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中 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 该小组将对理解生理学做出很大贡献 健康和疾病中铁的流动和利用的潜在过程 诸如铁超载和贫血、阿尔茨海默病和 恶毒。

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.