Dr. Stephen Duncan an investigator for $9 million collaborative grant to study cardiovascular disease

The Medical College of Wisconsin and the Perelman School of Medicine at the University of Pennsylvania received a five-year, $9 million grant in 2012 from the National Institutes of Health’s National Human Genome Research (NHGRI) and the National Heart Lung and Blood (NHLBI) Institute to study the role genetics plays in certain types of cardiovascular disease.

Stephen A. Duncan, DPhil, Professor of Cell Biology, Neurobiology and Anatomy; the Marcus Professor of Human and Molecular Genetics; and Director of the Medical College’s Program in Regenerative Medicine and Stem Cell Biology, will collaborate with Daniel J. Rader, MD, chief of the Division of Translational Medicine and Human Genetics, and Edward Morrisey, PhD, professor of medicine and cell and developmental biology at the Perelman School of Medicine at the University of Pennsylvania.

Cardiovascular disease is the number one killer of individuals in the United States. Atherosclerotic cardiovascular disease occurs when people build up fat, or lipids, in their arteries.

Genetic studies performed in 100,000 people have identified 95 specific genetic locations that appear to be associated with elevated lipid levels, which are controlled by the liver.

Dr. Duncan, Dr. Morrisey, and Dr. Rader’s groups have shown that they can take fat cells from adults, turn them into stem cells, or iPS cells, and then convert those cells into liver cells. The team will examine iPS-derived liver cells from 300 patients with defined genetic profiles. Those cells will then be used to determine why some patients with specific genetic mutations are predisposed to generating high levels of plasma lipids.

“We believe that the combined use of genetic analyses and advanced stem cell approaches will allow us to develop a clearer understanding of cardiovascular disease, which could lead to the production of new therapies,” Dr. Duncan said. “I am particularly thankful to the Marcus family, the Sophia Wolf Quadracci Memorial Fund, and the Phoebe and John D. Lewis Foundation, whose support was invaluable in the preliminary investigations that led to this project.”

This collaborative initiative brings together three research groups with unique talents, each of whom are leaders in their respective fields. Along with Dr. Duncan, who has more than 20 years of experience working with stem cells and the study of liver biology, the other group leaders in the team are Dr. Morrisey, who is also Scientific Director of the University of Pennsylvania Institute for Regenerative Medicine, and Dr. Rader, who is also the Edward S. Cooper, MD/ Norman Roosevelt and Elizabeth Meriwether McLure Professor of Medicine and Pharmacology and Associate Director of the Institute for Translational Medicine and Therapeutics at the Perelman School of Medicine at the University of Pennsylvania.

Helping lay the groundwork for this grant was new research conducted in Dr. Duncan’s laboratory by PhD student Max Cayo. The research team developed iPS-derived liver cells from a 14-year-old boy with familial hypercholesterolemia. They found that these new liver cells mirrored the disease characteristics of the boy’s actual liver cells and that they could be used to effectively study lipid and cholesterol metabolism, providing a platform for the identification of novel treatments of cardiovascular diseases.

It was the most careful examination of lipid and cholesterol functionality in human stem cell-derived liver cells to date and served as a feasibility study for the work proposed in the NHGRI/NHLBI grant. Cayo was first author of the paper “JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia,” which was published online in the September 2012 issue of the journal Hepatology.

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