Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide. In the United States, approximately 100,000 people have it, with heath care costs estimated to be $1.1 billion in the US alone. It is caused by a mutation in the ?-globin gene, causing glutamic acid to be substituted by valine. Because of this, when deoxygenated, the hemoglobin is able to polymerize, causing shape change of the red blood cell (RBC), RBC lysis, and innumerable other complications including acute and chronic pain, chronic anemia, multisystem organ damage, and a much shortened life expectancy. The symptoms appear shortly after birth, when fetal hemoglobin (HbF) levels decline, and are replaced by adult sickle hemoglobin. Because of this observation, much effort has been placed to induce fetal hemoglobin levels in those with SCD. Hydroxyurea, the only FDA approved drug for the treatment of SCD, is unfortunately effective in only about 50% of those who take it, and its mechanism is not clear. Therefore, our lab investigates alternate treatments for SCD in the SCD mouse model. It is believed that the red blood cell (RBC) is the most common cell in the body. In order to maintain a normal amount of hemoglobin to carry oxygen and remove carbon dioxide, adult humans, make more than 2 million red blood cells a second! This is the result of a highly orchestrated plan. Erythropoiesis in adult humans originates in the bone marrow and follows a path from progenitor to precursor to mature red blood cells. They follow the developmental scheme of the proerythroblast, followed by the basophilic erythroblast, the polychromatophilic erythroblast, and then the orthochromatic erythroblast. These are followed by reticulocytes, which are enucleated, and lose their organelles, and migrate from the marrow to the peripheral circulation. They normally account for 0.5 to 1.5% of all red blood cells, in those who are anemic, the percent increases. Reticulocytes have been found to have large vacuolar inclusions, which label for markers of the endoplasmic reticulum, Golgi, and mitochondria. It is thought that these vacuoles are eliminated by exocytosis and autophagy. PGC?1 is known to induce regulators of mitophagy and mitochondrial respiration. Recent studies on a knockout (Nix -/-) mouse also demonstrated the lack of mitophagy led to the short life span of RBCs Our preliminary data from untreated sickle cell mice show mature red blood cells retain mitochondria at a higher level than controls. The higher number of mitochondria rich reticulocytes in circulating blood could potentially promote the elevated levels of reactive oxygen species, changes in oxygen metabolism and the cell lysis seen in the disease. The molecular mechanism of increased mitochondria in red blood cells associated with SCD is not clear. Mitophagy regulated through the mammalian Target of Rapamycin (m-TOR) dependent and independent mitophagy pathway. This proposal seeks to provide pilot data that will link aberrant mitophagy with sickle cell pathology and develop new strategies for the treatment of SCD using mitophagy restoration drugs. Our goal is to obtain preliminary data that the reductions of mitochondrial retention in RBC will provide safe and effective therapy in SCD mouse.

Public Health Relevance

Sickle cell disease is an inherited blood disorder that affects millions of people worldwide. Individuals with sickle cell disease suffer from painful crises, chronic anemia, multisystem organ damage and shorter life span. This proposal seeks to develop new strategies for the treatment of SCD by correcting defective mitochondrial retention seen in the mature sickle red cell.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Research Grants (R03)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Program Officer
Hanspal, Manjit
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Schools of Medicine
United States
Zip Code
Jagadeeswaran, Ramasamy; Vazquez, Benjamin A; Thiruppathi, Muthusamy et al. (2017) Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease. Exp Hematol 50:46-52