Constance Tom Noguchi, Ph.D.
Molecular Cell Biology Section, Molecular Medicine Branch
Building 10, Room 9N319
10 Center Drive
Bethesda, MD 20814
Induction of erythropoietin production by low oxygen enables erythropoietin to act as a protective cytokine against hypoxic stress. Elevated erythropoietin stimulates survival, proliferation, and differentiation of blood stem cells/progenitor cells to form mature red blood cells. Erythropoietin activity in other tissues including endothelial, neural muscle, and fat suggests the potential for erythropoietin to act as a pleotrophic hypoxia responsive cytokine to facilitate tissue repair and wound healing. Erythropoietin stimulation of nitric oxide production in vascular endothelium contributes to increased oxygen delivery. Erythropoietin activity in non-erythroid tissue complements its function in erythroid and endothelial tissue to increase oxygen delivery by promoting oxygen consumption.
The purpose of these studies on erythropoietin biology is to determine endogenous erythropoietin activity in erythroid and non-erythroid tissue, including response to hypoxia, and the action of erythropoietin treatment to regulate red blood cell production, oxygen delivery, and other tissue responses.
Our lab investigates the role of cytokines in maintaining stem/progenitor cell characteristics. Molecular structure and processing related to cellular function, differentiation, and development are studied using molecular and cell biology, biochemical, and biophysical approaches. Emphasis is on transcriptional regulation and models of proliferation and differentiation. We are particularly interested in the function of the erythropoietin receptor and stress response in hematopoietic, neuronal, muscle, endothelial, fat, and other stem/progenitor cells. Other studies include differential globin gene expression related to the pathophysiology of sickle cell disease and other hemoglobinopathies.
Applying our Research
Erythropoietin has been available as cytokine treatment to increase red blood cell production for treatment of anemia in conditions such as chronic kidney disease for more than two decades. Demonstration of erythropoietin protective activity in animal models of brain and heart injury suggested potential use in stroke and cardiovascular disease. However, efforts to increase clinical applications of erythropoietin, including high dose erythropoietin treatment in anemic patients to increase hematocrit to normal levels in kidney disease and select cancers, led to awareness of adverse effects associated with high dose treatment. It also led to a requirement to reduce the recommended dose for erythropoietin therapy.
Full characterization of endogenous erythropoietin activity and erythropoietin response in tissues beyond red blood cell production will provide insight on its use to treat anemia and possibly related adverse events. It will also provide the potential application of erythropoietin administration for stroke, cardiovascular and other diseases, or tissue injury.
Need for Further Study
Erythropoietin activity in animal models and cultured cells has been useful in identifying erythropoietin action in various erythroid and other tissues. Areas for further study include endothelial response to erythropoietin to facilitate oxygen delivery and to promote tissue repair. Erythropoietin stimulation of nitric oxide production suggests a link between nitric oxide and erythropoietin activity. The manner in which erythropoietin regulated oxygen delivery acts with tissue-specific response to provide erythropoietin protective activity to injury in brain, heart, muscle and other tissue will clarify erythropoietin activity in tissue repair. Erythropoietin response in non-erythroid tissues contributes to regulation of metabolism, glucose level, insulin sensitivity, fat mass, and oxygen consumption. The role of specific tissues such as white fat and brain to these activities remain to be determined. In addition, regulation of energy expenditure and food intake by erythropoietin treatment suggests that the hypothalamus and neural response contribute to specific erythropoietin metabolic activity.
Understanding these aspects of erythropoietin action in addition to the response of blood cells and regulation of red blood cell production will clarify the role of stem cell/progenitor cell response to erythropoietin during development and tissue maintenance and repair. This gives rise to potential beneficial or adverse response to erythropoietin treatment for specific tissue injury or disease.
- Ph.D., The George Washington University, 1975
- B.A., University of California, Berkeley, 1970
Zhang Y, Rogers HM, Zhang X, Noguchi CT. Sex difference in mouse metabolic response to erythropoietin. FASEB J. 2017;31(6):2661-2673.
Alnaeeli M, Raaka BM, Gavrilova O, Teng R, Chanturiya T, Noguchi CT. Erythropoietin signaling: a novel regulator of white adipose tissue inflammation during diet-induced obesity. Diabetes. 2014;63(7):2415-31.
Wang L, Teng R, Di L, Rogers H, Wu H, Kopp JB, Noguchi CT. PPARα and Sirt1 mediate erythropoietin action in increasing metabolic activity and browning of white adipocytes to protect against obesity and metabolic disorders. Diabetes. 2013;62(12):4122-31.
Jia Y, Suzuki N, Yamamoto M, Gassmann M, Noguchi CT. Endogenous erythropoietin signaling facilitates skeletal muscle repair and recovery following pharmacologically induced damage. FASEB J. 2012;26(7):2847-58.
Teng R, Gavrilova O, Suzuki N, Chanturiya T, Schimel D, Hugendubler L, Mammen S, Yver DR, Cushman SW, Mueller E, Yamamoto M, Hsu LL, Noguchi CT. Disrupted erythropoietin signalling promotes obesity and alters hypothalamus proopiomelanocortin production. Nat Commun. 2011;2:520.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on September 12th, 2018