REGULATION OF HEPCIDIN BY IRON AND OXYGEN

描述(由申请人提供)： 该提案概述了过渡到独立调查员的三年培训计划。在她之前在加州大学洛杉矶分校托马斯·甘茨博士的实验室学习期间，申请者发展了铁代谢的背景，并获得了广泛的相关研究技能。她现在将利用导师的时间充分发展自己的研究想法，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。她还将扩大自己在研究伦理方面的教育。托马斯·甘茨将担任主要的科学导师。作为先天性免疫和铁代谢的先驱，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结合在一起。培训计划还包括来自铁代谢领域最著名的研究人员和导师之一的曾傑瑞·卡普兰博士和细菌和植物铁代谢专家萨贝哈·梅钱特博士的指导，梅钱特博士还将在正规教学和学术生涯发展方面提供指导。 海普西丁是一种关键的铁调节激素，也是一系列铁紊乱的致病因子。这项拟议的研究项目主要关注海普西丁如何受铁和缺氧的调节。这可能是当今铁代谢领域最重要的问题。具体来说，我们会： 1.铁对海普西丁合成的调节作用 1A.血凝素受体的鉴定(S) 1B.分析血红蛋白与TfR2和HFE可能的相互作用 1C。检查肝外铁传感器是否通过可溶性血凝素调节海普西丁的合成 1D。确定凝血酶反应所需的海普西丁启动子的元件 2.氧对海普西丁合成的调节作用 2A。确定缺氧诱导因子如何参与氧对海普西丁的调节 2B。鉴定低氧反应所需的海普西丁启动子元件 明确铁和氧调节海普西丁的分子途径对于了解全身铁稳态以及铁超负荷疾病的发病机制是必不可少的，并可能为设计新的诊断和治疗这些疾病的药物提供基础。

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.