To repair any piece of machinery – an airplane engine, a lawn mower, a computer motherboard – you first have to understand the function of each of its parts and how those parts work together. This is also true for the biological machinery that performs innumerable small tasks in the human cell to make the organs and tissues in our body function properly.
In her lab at the University of Kansas Medical Center, Robin Maser, Ph.D., Associate Professor of Clinical Laboratory Sciences At KU School of Health Professionals, he attempts to understand the function of a cellular protein known as polycystin-1 which, when damaged, is responsible for the inherited form of polycystic kidney disease (PKD) that accounts for 85% of PKD cases.
The fourth leading cause of kidney failure, PKD causes fluid-filled sacs to form in the kidneys and impair their function. It can also cause liver cysts, back and abdominal pain, high blood pressure, and cardiovascular problems.
The mutant polycysteine-1 protein involved in PKD is produced by a defective PKD1 gene. “The million-dollar question is, if the gene isn’t damaged and so the protein is working properly, what exactly is that protein going to do and how is it going to do that?” Maser said.
In her most recent study published in Proceedings of the National Academy of Sciences, Mazer and her colleagues have solved part of the puzzle. She and her colleagues have discovered the mechanism by which polycysteine-1 initiates cell signaling, an important form of communication from outside to inside cells.
Specifically, the portion of the polycystin-1 protein that extends outside the cell divides in two, subtracts one portion, and thus displays a small portion of the protein (called the stem or Single, which means “stinger” in German) that remain within the cell membrane. The stem then attaches to the remainder of the protein, which then activates cell signaling.
But if polycysteine-1 mutates, and cell signaling does not occur, the cell cannot adapt to its external environment and disease can occur.
Alan Yu, MB, B. said, “But the details are not nearly as important as the fact that Dr. Mazer has now discovered the possible central role of this protein, and by inferring what is responsible for causing PKD when it is mutated.”
Maser’s work was replicated in the lab using a kidney cell line by Yinglong Miao, Ph.D., associate professor in the Center for Computational Biology and the University of Kansas Department of Molecular Biosciences and an author on the study. Miao created a computer simulation of polycysteine-1, the results of which matched those of the Maser lab.
This work is based on research conducted by KU Medical Center decades ago. The Jared Grantham Kidney Institute is named after the famous doctor who conducted basic research into PKD. Maser, whose father died of PKD, was, ironically, working in a different field of research in the mid-1990s when James Calvet, PhD, deputy director of the Kidney Institute, was her postdoctoral advisor and began collaborating with Grantham. “I didn’t know anything about the disease,” Masser recalls. “And my father died much earlier. It shows how little knowledge is.”
Currently there is only one FDA approved drug for PKD, tolvaptan, but it is only approved for adults, it is not a treatment and has some uncomfortable side effects, including thirst and frequent urination.
Now that researchers understand this part of the disease process, this knowledge can be used as a basis for drug design. “If we understand [how the protein is supposed to function]Then we can design therapies that actually try to repair the function of the protein, rather than treat the symptoms.” “What we hope is to be able to make a drug that we can offer to people with PKD that will be able to restore polycysteine-1 signaling to a level sufficient to either inhibit the disease or prevention.