To repair any piece of machinery – an airplane engine, a lawn mower, a computer motherboard – you must first understand the function of each of its parts and how those parts work together. This is also true for the biological machinery that performs countless small tasks in the human cell to keep the organs and tissues of our body functioning properly.
In his lab at the University of Kansas Medical Center, Robin Maser, Ph.D., associate professor of clinical laboratory sciences at the KU School of Health Professions, tries to understand the function of a cellular protein known as polycystin-1 which, when damaged, is responsible for an inherited form of polycystic kidney disease (PKD) which accounts for 85% of PKD cases.
The fourth cause of kidney failure, PKD causes fluid-filled cysts to form in the kidneys and impair their function. It can also cause cysts in the liver, pain in the back and abdomen, high blood pressure and cardiovascular problems.
The mutant polycystin-1 protein involved in PKD is produced by a damaged PKD1 gene. “The million dollar question is, if the gene was not damaged and therefore the protein was working properly, what exactly would this protein do and how would it do it?” Maser said.
In his latest study, published in Proceedings of the National Academy of Sciences, Maser and his colleagues solved part of this puzzle. She and her colleagues discovered the mechanism by which polycystin-1 initiates cell signaling, a critical form of communication from the outside to the inside of cells.
Specifically, the part of the polycystin-1 protein that extends outside the cell splits in two, losing part and thus exposing a small part of the protein (called the stalk or clip, meaning “stinger” in German) that remains in the cell membrane. The stalk then attaches to the remaining part of the protein, which then triggers the activation of cell signaling.
But if polycystin-1 is mutated and cell signaling does not occur, the cell cannot adapt to its external environment and disease can occur.
The study “provides really elegant biochemistry and structural biology to show in detail how the protein does all of this,” said Alan Yu, MB, B.Chir., director of the Jared Grantham Kidney Institute at KU Medical Center. “But the details are not as important as the fact that Dr. Maser has now understood what the likely central role of this protein is and, by inference, what is responsible for PKD when it is mutated.”
Maser’s work in the lab using a kidney cell line was duplicated by Yinglong Miao, Ph.D., associate professor at the Center for Computational Biology and the Department of Molecular Biosciences at the University of Kansas and author of the study. Miao created computer simulations of polycystin-1, the results of which matched results from Maser’s lab.
This work is based on research conducted by the KU Medical Center for decades. The Jared Grantham Kidney Institute is named after the famous doctor who conducted basic research on PKD. Maser, whose own father died of PKD, was ironically working on another line of research in the mid-1990s when James Calvet, Ph.D., deputy director of the Kidney Institute, was his postdoctoral adviser and began to collaborate with Grantham. “I didn’t know anything about the disease,” Maser recalls. “And my father had died long before. This shows how little knowledge there is.
There is currently only one FDA-approved medication for PKD, tolvaptan, but it is only approved for adults, is not a cure, and has uncomfortable side effects including thirst and nausea. frequent urination.
Now that researchers understand this part of the disease process, this knowledge can serve as the basis for drug design. “If we understand [how the protein is supposed to function], we can then design therapies that, instead of treating the symptoms, actually attempt to repair the function of the protein,” Maser said. “What we’re hoping for is that we can make a drug that we can give to people with PKD that can restore polycystin-1 signaling to a level that’s sufficient to ameliorate the disease or prevent it.”