$1.5M grant funds research aimed at reducing strokes in children with sickle cell disease

September 30, 2010

A researcher from the biomedical engineering department operated by Georgia Tech and Emory University has received a $1.5 million NIH Director's New Innovator Award to support a project aimed at reducing the incidence of stroke in children with sickle cell disease. Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering, will use the National Institutes of Health (NIH) funding to develop models for identifying which children with the disease are at risk for stroke.

The first case of sickle cell disease was identified in 1910 and today it affects more than 70,000 Americans. It is seen mostly in persons of African descent, but also in individuals of Middle Eastern, Mediterranean, Central and South American, and Asian Indian heritage. Approximately 10 percent of children with sickle cell disease suffer a stroke. Having experienced one stroke, they are at high risk of having another.

"Current therapies to prevent strokes in children with sickle cell disease have substantial side effects, so we need to create better ways to predict which patients need intervention," said Platt, who is also a Georgia Cancer Coalition Distinguished Cancer Scholar. "My goal is to use experimental and clinical data to develop a mathematical model for predicting stroke risk in pediatric patients with sickle cell disease to allow for earlier intervention."

Now in its fourth year, the 2010 NIH Director's New Innovator Awards will support 52 exceptionally creative new investigators who propose highly innovative projects that have the potential for unusually high impact.

"NIH is pleased to be supporting early-stage investigators from across the country who are taking considered risks in a wide range of areas in order to accelerate research," said Francis S. Collins, M.D., Ph.D., director of the National Institutes of Health. "We look forward to the results of their work."

Platt's research project will integrate cell biology, clinical pediatric hematology, enzyme kinetic modeling and dynamics, predictive statistical regression modeling, biomechanics, tissue remodeling and personalized medicine.

"Successful integration of all these areas would significantly advance the diagnosis and therapeutic intervention of strokes in children with sickle cell disease in a way that has not been seen in the one hundred years since this disease was first identified," said Platt.

The disease hits close to home for Platt, whose brother was recently diagnosed with sickle cell trait -- meaning he inherited a sickle cell gene from one of his parents and a normal gene from the other. In Georgia, one in every 1,300 children is born with sickle cell disease.

Sickle cell disease is a genetic condition present at birth. It involves an altered gene that produces abnormal hemoglobin -- the protein that carries oxygen in the blood. In sickle cell disease, red blood cells become hard, sticky and "C" shaped. Sickle cells die early, which causes a constant shortage of red blood cells.

The abnormal cells also clog the flow in small blood vessels, causing chronic pain and other serious problems such as infections and acute chest syndrome. Strokes, however, occur in large arteries with high blood flow rates and other biomechanical parameters known to cause plaque formation in atherosclerosis. The damage caused by sickled red blood cells in the arteries and links to remodeling of the arteries have not been extensively studied.

To understand the coordination of the mechanisms that produce structural changes in the arterial wall leading to stroke, Platt plans to model sickle cell disease from the molecular level to the human level based on clinical data, novel biomarkers and patient outcomes. First, he plans to develop a quantitative model that will detail the activation and inactivation of proteases -- enzymes that break down proteins -- in the artery walls of individuals with sickle cell disease.

"I will focus on incorporating different cathepsins, elastin and collagens into the model," said Platt. "I plan to use an assay recently developed in my laboratory that reliably detects and quantifies mature cathepsins using a technique called gelatin zymography."

After determining which proteases play a role in sickle cell disease, Platt will then determine how biomechanical conditions of sickle cell disease, such as altered blood flow and red blood cell stiffness, affect cell-mediated remodeling of arteries by these proteases. This will be done in collaboration with Coulter Department professor Gilda Barabino. With this information, Platt can link quantitative measures of blood flow and inflammatory markers found in sickle cell disease to the narrowing of artery openings and associated protease remodeling.

These markers will first be validated with animal models of sickle cell disease, in collaboration with Solomon Ofori-Acquah, an assistant professor of pediatrics at Emory University and the Children's Healthcare of Atlanta Aflac Cancer Center and Blood Disorders Service. Further validation will come from blood samples collected from individuals with sickle cell disease, which will be provided by Beatrice Gee, medical director of the Hematology and Sickle Cell Program at Children's Healthcare of Atlanta at Hughes Spalding and an associate professor of clinical pediatrics at the Morehouse School of Medicine.

Overall, Platt will integrate biochemical and biomechanical mechanisms of cardiovascular disease with predictive mathematical models that robustly interpret clinical biomarkers to develop a personalized medicine protocol that will predict strokes in individuals with sickle cell disease and reveal new mechanisms for therapeutic targets. If these methods are successful, they could be expanded to broader categories of cardiovascular disease, such as atherosclerosis, myocardial infarctions and heart valve stenosis.
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Georgia Institute of Technology

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