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Building Potential
Two Studies by CHORI PI Break New Ground in Sickle Cell Research

While African tribes have known for thousands of years that their populations often suffered from a debilitating condition, the name Sickle Cell Disease (SCD) itself was not coined until 1910; it wasn’t until 1949 that SCD was associated with altered proteins, and not until 1956 that the point mutation in the DNA responsible for sickle cell disease was identified.

Now, just 50 years later – a mere moment on the timeline of scientific discovery – CHORI principal investigator Frans Kuypers, PhD and his colleagues have identified for the first time essential mechanisms of SCD pathogenesis that could ultimately provide invaluable clues in developing novel treatment protocols

Essential to lipid organization is a phospholipid called phosphatidylserine (PS). In healthy cells, PS is always maintained on the inside of the lipid membrane that comprises the outer surface of a red blood cell (RBC). When PS appears on the outside of the cell, however, it triggers the process of apoptosis, or cell death.

“That can be good or bad,” says Dr. Kuypers. “If you want a cell to be removed, it’s very good. But you don’t want it to happen under conditions that are not controlled, which is what happens in sickle cell disease.”

In fact, PS exposure can be directly related to nearly all of the painful and potentially fatal complications associated with SCD, such as vaso-occlusive episodes, acute chest syndrome, pulmonary hypertension and stroke. Two studies, published in the British Journal of Haematology, demonstrate both the conditions under which PS becomes exposed, and the key protein responsible for those conditions.

In the first, in collaboration with Dr. Kitty de Jong, Dr. Kuypers identified that sulphydryl modifications caused by oxidative stress can affect phospholipid scramblase activity.

“What we’ve demonstrated in this first paper is that oxidative stress, as well as alterations in calcium levels, are important triggers in the scrambling activity that causes PS exposure.”

While alternations in calcium levels and oxidative stress create the essential environment in which scrambling activity occurs, they are only part of the puzzle. The key player that normally maintains PS on the inside of the plasma membrane has not been identified – until now.

In the second paper, Dr. Kuypers, in collaboration with Dr. Eric Soupene, has identified two different protein isoforms responsible for transporting PS from the outside to the inside of RBCs. Thes proteins counteract scramblase activity and keep PS where it should normally be.

The identification of ths protein also known as the “flipase”, because it flips PS from the outer to the inner side is a groundbreaking discovery in terms of the long-term implications for the treatment of sickle cell disease.

As Dr. Kuypers explains, “Ultimately, with a better understanding of the underlying mechanisms that result in unwanted PS exposure, and with a better understanding of how the protein we’ve identified does what it does, you can learn how to trigger the PS exposure, or how to control PS exposure.”

Although the research is still in the realm of basic science, there is true potential to eventually treat sickle cell disease by being able to prevent PS exposure, or conversely, to treat conditions in which cells don’t die when they should, such as cancers, by being able to induce PS exposure.

Though that potential is still a long way from being realized, CHORI’s Center for Sickle Cell Disease and Thalassemia provides exactly the kind of bench-to-bedside research to make it so.

“We have such an active sickle cell and thalassemia research program at Children’s Hospital,” says Dr. Kuypers, “precisely because we have researchers working in basic science in my laboratory, who partner with such capable physicians as we have in the clinics. This teamwork really makes the difference”


Monday, May 16, 2011 11:33 PM

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