Adult bone marrow erythropoiesis is primarily homeostatic, constantly producing new erythrocytes throughout adult life. However, during fetal development and in response to acute anemia in adults the situation is dramatically different. At these times stress erythropoiesis predominates, which rapidly produces large numbers of new erythrocytes. Little is known about the mechanisms that regulate stress erythropoiesis in humans. My laboratory utilizes a murine model for stress erythropoiesis and has demonstrated that BMP4 dependent signals are required for the rapid expansion of a specialized population of stress erythroid progenitors during the recovery from acute anemia. These progenitors have greater potential to rapidly generate large numbers of new erythrocytes than bone marrow steady state progenitors. In this proposal we will further characterize the BMP4 dependent stress erythropoiesis pathway by taking advantage of a robust experimental system that utilizes erythroid recovery during the period immediately following bone marrow transplant. Our preliminary data show that this recovery is mediated by erythroid short-term radioprotective cells, which utilize the BMP4 dependent stress erythropoiesis pathway. In the first aim, we will examine the mechanisms that regulate BMP4 expression in the spleen during the recovery from bone marrow transplant. In the second aim, we will examine the role of Hedgehog and BMP4 signaling in the specification and expansion of stress erythroid progenitors in the spleen. While in the third aim, we will examine the regulation of Scl, Gata2 and Gata1 by Hedgehog, BMP4 and hypoxia. These studies will provide key basic information concerning the regulation of stress erythropoiesis, which can be built upon to develop new therapies to treat anemia.

Public Health Relevance

This project outlines experiments designed to investigate the mechanisms that regulate the rapid production of new red blood cells at times of acute need. The information gathered from this work will provide key basic information for the development of new therapies for anemia and other blood diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080040-03
Application #
8109905
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Bishop, Terry Rogers
Project Start
2009-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$315,495
Indirect Cost
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Xiang, Jie; Wu, Dai-Chen; Chen, Yuanting et al. (2015) In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors. Blood 125:1803-12
Gandhi, Ujjawal H; Kaushal, Naveen; Hegde, Shailaja et al. (2014) Selenium suppresses leukemia through the action of endogenous eicosanoids. Cancer Res 74:3890-901
Hegde, Shailaja; Hankey, Pamela; Paulson, Robert F (2012) Self-renewal of leukemia stem cells in Friend virus-induced erythroleukemia requires proviral insertional activation of Spi1 and hedgehog signaling but not mutation of p53. Stem Cells 30:121-30
Anderson, Nicole M; Berberovic, Zorana; Berndl, Elizabeth et al. (2012) Cytopenia induction by 5-fluorouracil identifies thrombopoietic mutants in sensitized ENU mutagenesis screens. Exp Hematol 40:48-60
Paulson, Robert F; Shi, Lei; Wu, Dai-Chen (2011) Stress erythropoiesis: new signals and new stress progenitor cells. Curr Opin Hematol 18:139-45
Kaushal, Naveen; Hegde, Shailaja; Lumadue, Jeanne et al. (2011) The regulation of erythropoiesis by selenium in mice. Antioxid Redox Signal 14:1403-12
Hegde, Narasimha V; Unger, Erica L; Jensen, Gordon L et al. (2011) Interrelationships between tissue iron status and erythropoiesis during postweaning development following neonatal iron deficiency in rats. Am J Physiol Gastrointest Liver Physiol 300:G470-6
Gandhi, Ujjawal H; Kaushal, Naveen; Ravindra, Kodihalli C et al. (2011) Selenoprotein-dependent up-regulation of hematopoietic prostaglandin D2 synthase in macrophages is mediated through the activation of peroxisome proliferator-activated receptor (PPAR) gamma. J Biol Chem 286:27471-82
Hughes, Michael R; Anderson, Nicole; Maltby, Steven et al. (2011) A novel ENU-generated truncation mutation lacking the spectrin-binding and C-terminal regulatory domains of Ank1 models severe hemolytic hereditary spherocytosis. Exp Hematol 39:305-20, 320.e1-2
Paulson, Robert F (2011) Erythropoiesis lagging? pIgA1 steps in to assist Epo. Nat Med 17:1346-8

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