Alan N. Schechter, M.D., Chief
Jeffery L. Miller, M.D.
Constance T. Noguchi, Ph.D.
Daniel G. Wright, M.D.
The Molecular Medicine Branch conducts research on fundamental mechanisms related to several human diseases. For many years, the primary focus has been on the genetic diseases of hemoglobin, including sickle cell anemia and thalassemia, but more recently it has broadened to other diseases of the erythroid lineage as well as a variety of cardiovascular conditions in which regulation of blood flow via nitric oxide and other signaling molecules could have important therapeutic consequences. Most of the work is laboratory-based, but branch members are also active investigators in multiple clinical protocols. Such clinical studies are paired with matching laboratory programs, and relate to a number of areas: (1) developing biomarkers to predict the severity of sickle cell disease and the etiology of acute and chronic pain as part of this condition, (2) understanding the regulation of fetal hemoglobin expression during development, (3) studying the effects of erythropoietin and other signaling molecules in erythroid cells, and (4) determining the interactions of intracellular and plasma hemoglobin with nitric oxide and nitrite ions in physiology and pathology. This final set of studies has recently been extended to include analyzing the effects of molecules such as nitrite on platelet function and blood flow in the brain.
The Molecular Biology and Genetics Section has focused on studies of nitric oxide metabolism and its role in disease pathophysiology and treatment over the past decade. Overall, the primary aims of this section are to show how erythrocytes and hemoglobin have major functions beyond oxygen transport and to understand how these substances may contribute to normal and pathological states. The section’s investigators have shown that reduction of nitrite ions by heme proteins, such as hemoglobin, is a major source of bioactive nitric oxide (NO) in the body, raising the possibility that nitrite might be used therapeutically in conditions where there is an effective depletion of this function. In particular, cell-free hemoglobin present in individuals with acute and chronic anemia may cause pathology by several mechanisms, including depletion of NO. Recent work has shown that NO is essential to the control of blood flow in the brain in response to various stimuli and has demonstrated that platelet reactivity is modulated by nitrite reduction to NO in the blood; both processes may be regulated by ascorbic acid and this is being tested.
The Molecular Cell Biology Section addresses non-erythroid effects of the hormone erythropoietin (Epo). The section’s staff has shown that many neuronal cells produce Epo and the Epo-receptor signaling pathway contributes to neural protection, especially in response to hypoxia, and also protects against traumatic brain injury. Epo is necessary for the proliferation of neural progenitor cells and, in animal models, Epo facilitates myoblast transplantation and helps protect heart function, in response to hypoxia, both functions appear to involve reciprocal effects of NO and Epo. More recently, section members have shown that Epo protects against obesity and abnormal glucose metabolism in rodents fed a high-fat diet. A new area of inquiry is the interaction of Epo with these pathways and the relevance of Epo to diabetes and its treatment.
The Molecular Genomics and Therapeutics Section primarily investigates normal and abnormal erythropoiesis. As a result of systemic transcriptome studies, this group has shown that levels of growth differentiation factor 15 serve as a marker of thalassemia disease severity because they reflect ineffective erythropoiesis, and presumably erythroid-cell apoptosis. Further studies of erythropoiesis have demonstrated that iron metabolism in erythroid cells is very specialized to these cells, a finding that may explain certain aspects of iron-deficiency anemia, including aspects of the mechanism of the recently discovered iron-regulatory hormone, hepcidin. In addition, studies of fetal hemoglobin levels among children with sickle cell disease have led to a new model for the control of this important clinical variable and have also produced data suggesting that hematological profiles before the age of six months can be used to predict disease severity and the need for treatment later in life. Work of this type provides a strong example of the interplay between clinical observations and fundamental molecular biology analyses, as well as demonstrating the benefits of employing a comprehensive approach to understanding human disease.