|Gregory J. Pazour, PhD|
Gregory J. Pazour, PhD, professor of molecular medicine, received the 2015 Lillian Jean Kaplan International Prize for Advancement in the Understanding of Polycystic Kidney Disease (PKD), for his discovery of the role cilia dysfunction plays in the disease. The award is a partnership between the PKD Foundation and the International Society of Nephrology (ISN) and recognizes a medical professional or researcher exhibiting excellence and leadership in PKD research and whose work demonstrates tangible achievement toward improving knowledge and treatment of PKD.
“The Kaplan Prize, which is the most prestigious prize in the polycystic kidney field, is a long-overdue recognition of Greg’s enormous impact,” said George B. Witman, PhD, the George F. Booth Chair in the Basic Sciences and professor of molecular, cell, & cancer biology. “Greg’s pioneering studies demonstrating the connection between cilia and PKD provided the foundation for much of the work done in the field over the last decade.”
PKD is a one of the most common life-threatening genetic disorders in the world, affecting an estimated 12.5 million people. Characterized by the presence of multiple cysts on the kidneys, PKD eventually leads to kidney failure. There is no treatment or cure for PKD. Once a person has kidney failure, dialysis or transplants are the only options to treat the damage the disease has caused. Approximately 10 percent of the people diagnosed with PKD have no family history of the disease, with PKD developing as a spontaneous mutation. Parents with PDK have a 50 percent chance of passing it on to each of their children. A relatively rare form of PKD, autosomal recessive polycystic kidney disease, affects approximately one in 20,000 children, and often causes death within the first month of life.
An expert in cilia function and assembly, Dr. Pazour was the first to draw an unexpected link between cilia dysfunction and PKD. Cilia are short, hair like appendages that project from the cell body and are classified as either motile or nonmotile, also known as primary, cilia. This discovery led to the understanding that primary cilia, once thought to be an evolutionary vestigial part of the cell, act as important sensory antennae, relaying signals to the cell body and are essential to the function of many of the body’s organs. Since its first published association to PDK in 2000, cilia dysfunction has been identified in at least a dozen other genetic diseases. Collectively, these diseases are now known as ciliopathies.
“Greg’s discovery that defects in kidney cilia cause PKD was really just the tip of the iceberg,” said Dr. Witman. “Scientists had long known that cilia are present in many tissues throughout our bodies; Greg’s studies predicted that defects in cilia also should affect the other tissues in which cilia occur. Indeed, subsequent research by Greg and others has now shown that defects in cilia cause many other diseases, including blindness, congenital heart disease, skeletal abnormalities and cognitive impairment, to name just a few.”
In the late 1990s, Pazour was studying the proteins involved in intraflagellar transport (IFT) in the green alga Chlamydomonas, a model system for mammalian cilia. Working with Witman; Joel Rosenbaum, PhD, professor of molecular, cellular and developmental biology at Yale University, and Douglas G. Cole, PhD, professor of biological sciences at the University of Idaho, Pazour made the unexpected discovery that the Tg737 polycystic kidney disease gene encoded the intraflagellar transport protein IFT88. It turned out that this gene is required for cilia assembly in both Chlamydomonas and in the mouse kidney. Mutations in the gene resulted in short stubs of kidney cilia in mice. Further investigation revealed that the basic defect in mice with the Tg737 mutation was an inability to form cilia due to a defect in ITF and this led to PKD. Pazour later showed that polycystin-2, the protein encoded by the human autosomal dominant PKD2 gene, is localized to cilia.
Although not widely appreciated at the time, the epithelial cells lining the ducts and tubules of the mammalian kidney have primary cilia. Together, these studies laid the groundwork for the current appreciation of the role cilia play in PKD and helped establish that the primary cilium is a sensory organelle. Pazour’s laboratory is now focused on understanding the functions of the intraflagellar transport proteins using the mouse model. This work has established that cilia play critical roles in many organs including the heart and eye.
Pazour came to UMass Medical School from the Worcester Foundation for Biomedical Research, where he was a postdoctoral fellow. He received his PhD in biochemistry from the University of Minnesota in 1991 and an undergraduate degree in chemistry and biology from South Dakota State University.
The Kaplan award was established in 2002 by the PKD Foundation and the ISN through the generosity of Thomas Kaplan in memory of his mother, Lillian Jean Kaplan, who had PKD and died in 2002. The mission of the Kaplan award is to stimulate members of the global scientific and medical communities to increase or begin research leading to a PKD treatment and cure, generate momentum in the PKD field, and produce positive public awareness about PKD. The awards presentation took place at the ISN World Congress of Nephrology in Cape Town, South Africa, on March 15.
Pazour shares the 2015 Kaplan Award with Peter Igarashi, MD, the Nesbitt Chair and Head of the Department of Medicine at the University of Minnesota Medical School. Dr. Igarashi identified new proteins that control genes and characterized their roles in cystic kidney disease. In addition, Igarashi has studied the role of the primary cilium in the progression of PKD.