REGULATION OF HEPCIDIN BY IRON AND OXYGEN

描述（由申请人提供）： 该提案概述了向独立调查员过渡的三年培训计划。在加州大学洛杉矶分校Tomas Ganz博士的实验室学习期间，申请人发展了铁代谢的背景，并获得了广泛的相关研究技能。她现在将利用辅导期充分发展自己的研究思路，学习实验室管理和战略规划技能，并获得独立资金建立自己的实验室。她还将扩大她在研究道德教育。托马斯·甘茨将担任主要的科学导师。作为先天免疫和铁代谢领域的先驱，甘茨博士将令人印象深刻的科学和医学知识与高超的教学和管理技能相结合。培训计划还包括来自Jerry Kaplan博士的指导，Jerry Kaplan博士是铁代谢领域最杰出的研究人员和导师之一，Sabeeha Merchant博士是细菌和植物铁代谢专家，他还将提供正式教学和学术职业发展方面的指导。 铁调素是关键的铁调节激素，也是一系列铁紊乱的致病因子。拟议的研究项目集中在铁调素是如何通过铁和缺氧调节。这可能是当今铁代谢领域最重要的问题。具体而言，我们将： 1.检查铁对铁调素合成的调节 1a.鉴别血幼素受体 1b.分析血幼素与TfR2和HFE的可能相互作用 1c.检查肝外铁传感器是否通过可溶性血幼素调节铁调素合成 1d.确定hemojuvelin反应所需的hepcidin启动子元件 2.检查氧对铁调素合成的调节 2a.确定HIF如何参与氧对铁调素的调节 2b.铁调素启动子缺氧反应所必需元件的鉴定 确定铁调素的铁和氧调节的分子途径是必要的了解系统性铁稳态以及铁超载疾病的发病机制，并可能提供新的诊断和治疗这些疾病的药物设计的基础。

DESCRIPTION (provided by applicant): This proposal outlines a three year training plan for transition to an independent investigator. During her previous studies in the laboratory of Dr. Tomas Ganz at the UCLA, the applicant developed a background in iron metabolism and acquired extensive related research skills. She will now use the mentored period to fully develop her own research ideas, learn laboratory management and strategic planning skills, and obtain independent funding to establish her own laboratory. She will also broaden her education in research ethics. Tomas Ganz will serve as the main scientific mentor. A pioneer in innate immunity and iron metabolism, Dr. Ganz combines impressive scientific and medical knowledge with superb teaching and management skills. The training plan also involves mentorship from Dr. Jerry Kaplan, one of the most prominent investigators and mentors in the field of iron metabolism, and Dr. Sabeeha Merchant, an expert on bacterial and plant iron metabolism who will also provide guidance in formal teaching and academic career development. Hepcidin is the key iron-regulatory hormone and the pathogenic factor in a spectrum of iron disorders. The proposed research project focuses on how hepcidin is regulated by iron and hypoxia. This is perhaps the most important question in the field of iron metabolism today. Specifically, we will: 1. Examine the regulation of hepcidin synthesis by iron 1a. Identify the hemojuvelin receptor(s) 1b. Analyze possible interactions of hemojuvelin with TfR2 and HFE 1c. Examine whether an extrahepatic iron sensor modulates hepcidin synthesis via soluble hemojuvelin 1d. Identify the elements of the hepcidin promoter needed for the response to hemojuvelin 2. Examine the regulation of hepcidin synthesis by oxygen 2a. Determine how HIF is involved in hepcidin regulation by oxygen 2b. Identify the elements of hepcidin promoter necessary for the response to hypoxia Defining the molecular pathways of hepcidin regulation by iron and oxygen is essential for the understanding of systemic iron homeostasis as well as the pathogenesis of iron overload diseases, and may provide the foundation for design of new agents for the diagnosis and treatment of these disorders.