Regulation of Heme Uptake and Transport in Caco-2 Cells

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DESCRIPTION (provided by applicant): The overall goal of this proposal includes a plan to foster the career development of Dr. Aliye Uc while undertaking the investigation of intestinal heme uptake and transport through the intestines. Dr. Uc's long term career goal is to develop the research skills and experience to become an independent clinician scientist, capable of making meaningful contribution to biomedical sciences. This award would allow her to fulfill her immediate goals for furthering her understanding of heme-intestinal epithelial cell interactions at a molecular level through course work and attaining new research skills in cellular and molecular biology. This award would enable Dr. Uc to continue her investigation on the interactions of heme with the intestinal epithelium, its effect on electrolyte transport and possible role of oxidative stress in modulating this function. This career development plan would take place at the University of Iowa, an ideal environment for Dr. Uc's development as a clinical scientist, with Dr. Bradley E. Britigan serving as her primary mentor and Dr. John B. Stokes acting as co-mentor. This environment will provide Dr. Uc both resources and full access to critical expertise, needed to make significant contribution in the area of her research interest. The proposed research project investigates the cellular mechanisms involved in absorption and transcellular transport of heme in a well-established intestinal epithelial cell model, Caco-2 cells. Heme provides the majority of body's iron, but little is known about its absorption through the intestines. It is hypothesized that heme is acquired and transported in both directions (apical to basolateral and vice versa) by the intestinal epithelial cells via an active process that is also involved in electrolyte transport. This concept will be tested by the pursuit of the following Specific Aims: 1) Determine the mechanisms involved in intestinal epithelial heme uptake and the role of HO-1, intracellular heme and iron levels in regulating this process; 2) Determine the mechanisms involved in transcellular intestinal epithelial cell heme transport and the role of HO-1, intracellular heme and iron levels in regulating this process; and 3) Determine the electrolyte transporter(s) associated with the transport of heme. These studies will provide new insight into understanding heme transport through intestines in normal and disease states (e.g., hereditary hemochromatosis, iron overload secondary to blood transfusions) and explore the role of intestinal epithelial cell bi-directional heme movement on the regulation of iron stores.