The principle investigator, Grant Bullock, M.D., Ph.D., F.A.C.P., is a Clinical Instructor and member of the Faculty in the Department of Pathology at the University of Virginia (UVA). This K08 will support this investigator's transition to scientific independence in the field of anemia research. THE ENVIRONMENT: UVA's Pathology Department within the UVA School of Medicine is part of a large well funded biomedical research center with state-of-the-art core facilities and faculty with a history of effectively training clinician scientists. THE MENTOR: Professor Adam Goldfarb, M.D., F.A.C.P., is an ideal scientific and career mentor because he is an experienced leader in the field of molecular and cellular hematology and also is an expert practicing hematopathologist. In addition, an advisory committee of clinician scientists will meet with the candidate to provide scientific and career advice. The institution, mentor and the advisory committee members are committed to the success of the candidate. CAREER DEVELOPMENT/TRAINING ACTIVITIES: This 4- year career development plan will complete Dr. Bullock's transition to scientific independence as an academic hematopathologist. Mentoring will be more focused and formal during the first 2 years of the award and maintained at a lower intensity during the last 2 years of the award to facilitate scientific growth. A major goal of the independent research strategy described in this proposal is to obtain R01 funding during the third year. RESEARCH PLAN: Erythropoietin (Epo) is an essential cytokine for efficient red blood cell (rbc) production. Iron deficiency suppresses Epo-mediated rbc production by an unknown mechanism and causes anemia despite elevated serum Epo levels. The Epo receptor (EpoR) generates both inhibitory and stimulatory signals that suppress or promote rbc production, respectively. Iron deficiency may suppress rbc production by enforcing inhibitory signals generated by the EpoR. In this proposal we will determine the effects of iron deficiency on EpoR signaling using in vivo mouse models and physiologically relevant human cell culture models of iron deficiency anemia. Anemia affects the quality of life and the life expectancy of millions of people in the U.S. Many patients are either intolerant or unresponsive to available treatments, so alternative strategies are needed. Understanding how iron deficiency alters EpoR signaling pathways will provide new therapeutic targets for future anemia treatment strategies.
Anemia decreases the quality and the length of life of millions of people in the U.S. The growth factor erythropoietin (Epo) and the micronutrient iron are used to treat anemia, but these treatments do not help all anemic patients. Epo and iron can have harmful or fatal side-effects in some patients. This research study on the relationship between iron and Epo will provide new options for treating anemia.
|Khalil, Shadi; Delehanty, Lorrie; Grado, Stephen et al. (2018) Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor. J Exp Med 215:661-679|
|Richardson, Chanté L; Delehanty, Lorrie L; Bullock, Grant C et al. (2013) Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response. J Clin Invest 123:3614-23|
|Delehanty, Lorrie L; Bullock, Grant C; Goldfarb, Adam N (2012) Protein kinase D-HDAC5 signaling regulates erythropoiesis and contributes to erythropoietin cross-talk with GATA1. Blood 120:4219-28|
|Talbot, Anne-Laure; Bullock, Grant C; Delehanty, Lorrie L et al. (2011) Aconitase regulation of erythropoiesis correlates with a novel licensing function in erythropoietin-induced ERK signaling. PLoS One 6:e23850|
|Bullock, Grant C; Delehanty, Lorrie L; Talbot, Anne-Laure et al. (2010) Iron control of erythroid development by a novel aconitase-associated regulatory pathway. Blood 116:97-108|