A fresh look at polycystic kidney disease

Virtual tissue technology helps Indiana University researchers find new drug target

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BLOOMINGTON, Ind.—Using virtual tissue technology, researchers at Indiana University (IU) have gotten new insight into polycystic kidney disease and identified a new drug target for the condition, which currently has no U.S. Food and Drug Administration-approved treatment and affects 200,000 people a year in the United States alone.
The study, which appears in the journal Molecular Biology of the Cell, finds that errors in how cells stick together cause two different kinds of cysts in the kidneys. These cysts can cause a kidney, which is generally the size of a fist and weighs less than a pound, to enlarge to the size of a football weighing 20 to 30 pounds. At this time, the only way to delay death from polycystic kidney disease is through dialysis or a transplant.
“This is the first study to show the actual cell behaviors caused by mutations in genes causally linked to polycystic kidney disease, an important new step in the path towards treatment,” said Dr. Robert L. Bacallao, associate professor of medicine at the IU School of Medicine in Indianapolis.
The technology used for this study was developed by the Biocomplexity Institute at the IU School of Informatics and Computing, directed by James A. Glazier, professor in the IU Bloomington Department of Intelligent Systems Engineering. Julio Belmonte and Sherry G. Clendenon of the Biocomplexity Institute are the primary authors on the paper.
Glazier’s team started with Bacallao’s medical research data, using an open-source software program called CompuCell3D, developed by Maciej Swat of the Biocomplexity Institute, who is also a co-author on the paper, to create a virtual nephron (the core, tube-shaped functional unit of the kidney). This computer model was able to simulate cell activity triggered by cell mutations in PKD1 and PKD2, the genes implicated in polycystic kidney disease.
“Not many medical researchers are employing virtual tissue technology,” Glazier said. “The majority of researchers who use these simulations are pursuing basic science. So it’s extremely exciting to apply the technology to research directed at identifying drug targets to help people suffering from a specific disease.”
The study found that two types of change to the cells in the nephron cause cysts to develop, and both relate to how cells stick together. In the first scenario, cells fail to stick together, which is referred to as “reduced cell adhesion.” In the second, cell stick normally but fail to respond to contact, which is known as “loss of contact inhibitions.”
Cysts that formed as a result of reduced cell adhesion were mushroom-shaped, with a stalk and a cap that made up the bulk of the cyst, while cysts developing from loss of contact inhibitions built up like plaques along the walls of a nephron.
After running the simulations at IU Bloomington, Bacallao was able to confirm the cyst growth predictions seen in the virtual cysts in experiments by using real human cells cultivated from polycystic kidneys from patients at the IU School of Medicine.
“The computer predictions were absolutely correct,” said Bacallao, who estimated that the same experiments, which took several weeks, would have required 10 to 20 years to conduct in mice.
This study is the first to confirm the existence of two different types of cysts. According to Bacallao, the only reference to this is in a description of dissected polycystic kidneys from 1972.
“Now that we know that we’re looking at two different types of cyst that develop in two different ways, we will refine the computer modeling to identify the specific molecular signals leading to each type of cyst,” Glazier said. “Identifying this mode of action is a key step toward finding a drug treatment to delay or prevent cyst development.”
Other authors on the paper are Guilherme M. Oliveira and Srividhya Jeyaraman, research associates at the Biocomplexity Institute, and Evan V. Greene, an undergraduate at Swarthmore College, who spent the summer as an intern in Ballacao’s lab at the IU School of Medicine.
This research was supported in part by the National Institutes of Health’s National Institute of General Medical Sciences, the Falk Foundation and the IU Collaborative Research Grant Program. A portion of the tissue simulations were conducted with assistance from IU’s supercomputer, Big Red II. Ballacao is also a co-investigator on a clinical trial on polycystic kidney disease in collaboration Bonnie Blazer-Yost, a professor of biology at Indiana University-Purdue University Indianapolis.

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