- Dean, FAES (Foundation for Advanced Education in the Sciences, Inc.) Graduate School at the NIH, 1999-present
- Research Physicist, Laboratory of Chemical Biology, NIDDK, 1985-present
- NRSA Fellowship, National Institute of General Medical Sciences, Laboratory of Chemical Biology, NIAMDD, 1975-1977
- Ph.D., the George Washington University, 1975
- B.A., University of California, Berkeley, 1970
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.
- Sex difference in mouse metabolic response to erythropoietin.
- Zhang Y, Rogers HM, Zhang X, Noguchi CT.
- FASEB J (2017 Jun) 31:2661-2673. Abstract/Full Text
- Erythropoietin signaling: a novel regulator of white adipose tissue inflammation during diet-induced obesity.
- Alnaeeli M, Raaka BM, Gavrilova O, Teng R, Chanturiya T, Noguchi CT.
- Diabetes (2014 Jul) 63:2415-31. Abstract/Full Text
Research in Plain Language
Stem cells and progenitor cells have the remarkable ability to develop into different cell types. They offer the potential to provide a renewable source of replacement cells to treat diseases, conditions, and disabilities. We use molecular and cell biology, biochemical, and biophysical approaches to learn how these cells work. We are also particularly interested in the role of cytokines, proteins that trigger the initial development of stem and progenitor cells into different cell types. Our research allows us to build models of how these processes work.
One focus of our lab’s research is on the way in which a stem cell produces a red blood cell offspring. Erythropoietin, produced in the kidney, is the cytokine that regulates the daily production of 200 billion new red blood cells. These red blood cells are important because they carry oxygen from the lungs to tissues. In our lab we investigate many roles of erythropoietin such as the following:
- When oxygen levels are low, erythropoietin is triggered to increase red blood cell formation. As more red blood cells are formed, more oxygen can be moved from the lungs to tissues. This increases overall oxygen levels in the body.
- Erythropoietin stimulates endothelial cells to produce increased nitric oxide production; this regulates blood flow and contributes to increasing oxygen delivery. We relate this activity to a protective effect in a mouse model of heart ischemic injury (blocked blood flow).
- Erythropoietin can stimulate muscle progenitor cells to promote wound healing in a mouse model of skeletal muscle injury.
- In the brain, erythropoietin can stimulate the proliferation of neural progenitor cells and the survival of neurons to provide protection in mouse models of ischemic injury.
- Erythropoietin has metabolic activity that results in increased whole body oxygen consumption. Circulating erythropoietin produced in the body contributes to the regulation of fat mass and blood glucose levels. Mice with erythropoietin activity restricted to red blood cell production develop obesity and insulin resistance.
- Increased erythropoietin treatment, especially in obese mice, increases energy expenditure and activity, reduces food intake, and reduces fat mass. We examine the specific contributions of fat tissue response to erythropoietin in the regulation of metabolism. We also examine the specific contributions of hypothalamus response to erythropoietin in the regulation of food intake and energy expenditure.
Other studies in our lab focus on the activity of the globin gene family. Globin genes are components of hemoglobin, the molecule that carries oxygen. These genes make up 98 percent of the protein in red blood cells that transport oxygen in the bloodstream. In particular, we want to understand the changes in hemoglobin function observed in sickle cell disease and other diseases related to hemoglobin abnormalities.