REGULATION OF HEPCIDIN BY IRON AND OXYGEN

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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.