UTHealth scientists working to learn more about the fundamental causes of sickle cell disease from left are Drs. Anren Song, Kaiqi Sun, Yang Xia, and Yujin Zhang.
UTHealth scientists working to learn more about the fundamental causes of sickle cell disease from left are Drs. Anren Song, Kaiqi Sun, Yang Xia, and Yujin Zhang.

New preclinical research on the molecular mechanisms responsible for sickle cell disease could aid efforts to develop much needed treatments for this devastating blood disorder that affects millions worldwide.

An international research team led by biochemists at the Medical School reduced the sickling of red blood cells in a mouse model of the disease. Results of the study appear in The Journal of Clinical Investigation.

The scientists did this by manipulating a small molecule known as sphingosine-1-phosphate (S1P), which they report is found in elevated levels in people with sickle cell disease.

“Our research could lead to therapeutic opportunities,” said Dr. Yang Xia, the study’s senior author and a professor in the Department of Biochemistry and Molecular Biology. “We validated our findings in isolated blood cells from patients with sickle cell disease.”

The sickling of red blood cells is the hallmark of this disease. Normally shaped like a donut, the diseased cells instead have a crescent-like appearance. This can lead to anemia, chest pain, lung problems, and stroke.

Xia’s lab screened approximately 7,000 metabolites for functional differences between sickle cell disease mice and controls. They found that sickle cell disease significantly increases S1P and that S1P is generated by sphingosine kinase 1 (SphK1).

They are directly proportional, meaning the more SphK1, the more S1P, and vice versa, Xia said.

When SphK1 was inhibited in a mouse model of sickle cell disease, red blood cells lived longer and had less sickling. When the scientists treated blood samples taken from sickle cell disease patients with SphK1 inhibitors, the investigators found a significant reduction in the number of sickle cells.

Extending the cells’ life span is particularly important because diseased cells only last from 10 to 20 days compared to about 120 days for healthy cells in humans. Reducing the sickling is also significant because sickled cells are more prone to being damaged when passing through narrow capillaries. This can cause anemia and other dangerous complications.

“This work could lead to novel treatments for sickle cell disease,” said Dr. Harinder Juneja, study co-author and director of hematology at McGovern Medical School and Memorial Hermann-Texas Medical Center.

At the present time, hydroxyurea is the only Food and Drug Administration-approved medication that decreases the number of pain crises and episodes of acute chest syndrome.

“The study has identified a lipid bioactive molecule involved in sickling and disease progression. The study provides a better understanding of the pathogenesis of the disease and reveals a new therapeutic target,” Juneja said.

Dr. Rod Kellems, study co-author and chair of the Department of Biochemistry and Molecular Biology, added, “This research provides insight into how red blood cells work, revealing that SphK1-mediated elevation of S1P contributes to sickling and promotes disease progression and highlights potential therapeutic opportunities for sickle cell disease.”

Other UTHealth co-authors include Drs. Yujin Zhang, Ah-Lim Tsai, Modupe Idowu, Jianping Jin, Anren Song, Kaiqi Sun, Wenzheng Zhang, Vladimir Berka, Mikhail Bogdanov, Wei Wang, and William Dowhan, John S. Dunn Chair in Biochemistry & Molecular Biology, and Chonghua Li .

Additional co-authors include Drs. Chen Ning and Weiru Zhang the First Xiangya Hospital, Central South University, Changsha, Hunan, China; Dr. Qibo Zhang, Michael Milburn and Dr. Danny Alexander, Metabolon Inc., Durham, N.C; Mostafa Ahmed and Martin Safo, Virginia Commonwealth University, Richmond, Va.; Han Lin, Dr. Jun Zhang, and Dr. Pumin Zhang, Baylor College of Medicine; Dr. Osheiza Abdulmalik, Children’s Hospital of Philadelphia; and Dr. Gregory Kato, National Heart, Lung, and Blood Institute.

Xia, Kellems, Jin, Bogdanov, Wenzheng Zhang, and Dowhan are on the faculty of The University of Texas Graduate School of Biomedical Sciences at Houston.

The study titled “Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression” received support from National Institutes of Health grants (HL119549, P01HL114457, DK077748, HL11354, DK083559, HL095820), the American Heart Association (10GRNT3760081 and 12IRG9150001 and China Scholarship Council (2009637520).

-Rob Cahill, Office of Public Affairs, Media Relations