Date of Award

9-30-2010

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Howard Pearson, MD

Second Advisor

Jeffrey Gruen, MD

Abstract

OVEREXPRESSION OF HFE IN THE ERYTHROID COMPARTMENT CAUSES TRANSIENT ANEMIA IN MURINE MODELS WITH HFE-RELATED HEMOCHROMATOSIS. Gregory M. Blanton. Childrens Cancer & Blood Foundations Laboratories, Jaffe Genetics Center, Weill Cornell Medical College, New York, NY. (Sponsored by Howard A. Pearson, Department of Pediatrics, Yale University School of Medicine). The high Fe (HFE) gene, known to be strongly involved in iron-loading disorders such as hemochromatosis, interacts with transferrin receptor 1 (TFR1). TFR1 is highly expressed in erythroid precursors. Because some erythroid anomalies have been reported in hemochromatosis patients, a large investigation attempting to characterize erythropoiesis in HFE knockout (HFE-KO) mice in detail was undertaken at Weill Cornell Medical College. Initial experiments suggested that general overexpression of HFE in the bone marrow resulted in anemia. When it was discovered that HFE was expressed in both macrophages and erythroid precursors, a second set of experiments attempted to determine whether HFE overexpression in one of these two cell lines would duplicate the findings from general expression in the bone marrow. It was hypothesized that overexpression in the erythroid compartment, vice in the macrophages, would duplicate the anemia. For this investigation, a lentiviral vector was constructed to be erythroid-specific and to transduce murine bone marrow from HFE-KO animals. The animals were phlebotomized at two and three months post-transplant, and their hematologic parameters were analyzed. Only four animals were involved in the experimental arm; two animals did demonstrate a transient anemia and two did not. The investigation raised the possibility of expected results, but further studies are necessary to confirm these expectations.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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