Project Summary: The proposed University of Utah Cooperative Centers of Excellence in Hematology (CCEH) brings together 38 investigators whose research activities are focused on various aspects of iron and heme metabolism and non- malignant hematology. Iron plays an essential role in many biological processes including heme synthesis, oxygen transport, cellular respiration and DNA synthesis. Malregulation of iron homeostasis, either from deficiency or excess, results in disease. Heme is a key component of hemoglobin and other hemoproteins, but heme also plays a regulatory role in a number of metabolic pathways. Disorders of heme biosynthesis are responsible for an important group of human diseases, namely the porphyrias. The Utah Center for Iron and Heme Disorders (CIHD) will support the activities of a Research Base of 38 investigators whose research projects focus on the roles of iron, porphyrins and heme in eukaryotic metabolism. The activities of center members encompass both basic and clinical studies designed to identify disease mechanisms. To accomplish our goals, we propose an Administrative Core and four Biomedical Research Cores. The majority of the cores are already present and have been adjusted to meet the needs of the CIHD. These include: an Iron and Heme Core, which can assay and quantitate metals, porphyrins, heme biosynthetic enzymes and iron-binding and other proteins; a Metabolomics Core, which provides metabolomic phenotyping and molecular identification; a Mutation Generation and Detection Core, which provides cutting edge genome editing through CRISPR and TALEN reagents; and a new core in this renewal, the Protein-Metabolite Interactomics Core that provides proteomics services but adds the unique technology of identification of metabolites that interact with a protein and may post-translationally modify the protein in novel ways. The services provided by these cores will enable individual investigators to: 1) identify the role of genes in hematopoiesis or iron overload; 2) determine the effects of gene modification or mutations on metabolism in cultured cells or biological fluids; and 3) identify at the biochemical level the effect of mutations or conditions that affect iron and heme homeostasis on all levels. The Administrative Core will provide budgetary and scientific guidance to CIHD activities. Core recharge fees will be used to enhance and expand core operations. An Enrichment Program is designed for trainees and young investigators in the fields of nonmalignant hematology and for senior investigators who wish to enter this field. The Research Base is drawn from both the University of Utah and other institutions, with half of the members belonging to institutions outside of Utah. We have increased the Research base from 22 to 38 with the addition of ~4 investigators each year. The goals of the CIHD are to be a national resource for studies involving iron and heme and to inspire the next generation of investigators focu...