NOVEL DISCOVERY BY UMASS MEDICAL SCHOOL SCIENTISTS HELPS UNLOCK SECRETS OF POLYCYSTIC KIDNEY DISEASE

Findings about development of kidneys to be published in Current Biology

June 6, 2002

WORCESTER, Mass. ¾ In a study published in the June 4, 2002 issue of the journal Current Biology, a research team led by Gregory Pazour, PhD, Assistant Professor of Cell Biology, and George Witman, PhD, Professor of Cell Biology and the George F. Booth Chair in the Basic Sciences at the University of Massachusetts Medical School, describes new results that provide insight into the cause of polycystic kidney disease – a devastating genetic disorder that affects over 12.5 million people worldwide.  The Current Biology paper reports that a protein called polycystin-2, previously shown to cause polycystic kidney disease when defective in humans, is present on tiny hair-like structures – termed cilia – that extend from the surfaces of human kidney cells.  The findings yield important new clues about how polycystic kidney disease develops.

Unlike the better-known cilia of the human respiratory tract, which continuously beat back and forth to move mucus and foreign particles up and out of the lungs, the kidney cilia do not move.  As a result, some researchers had dismissed them as evolutionary relics that had lost their function.  However, the Pazour-Witman team reported two years ago that defects in kidney cilia assembly could cause polycystic kidney disease in mice – suggesting that the cilia do have an important function in the kidney.  The new discovery demonstrates a link between the cause of kidney disease in mice and humans, and reveals at least one function of the kidney cilia: relaying signals that control cell growth.  “It is now clear that polycystic kidney disease can result from either a defect in polycystin-2, or from a defect in the cilia to which polycystin-2 is targeted” said Witman.  “Polycystin-2 is known to generate a signal that controls the growth and differentiation polycystin-2 to receive a yet unknown signal, and then pass that signal on to the cell to control its of kidney cells.  Our current findings indicate that the kidney cilia act as antennae that use growth.  Defects in this signal reception and transmission lead to abnormal proliferation of kidney cells and the formation of kidney cysts.” 

The work of Pazour and Witman, along with co-authors Jovenal San Agustin, PhD, and John Follit, BS, of UMMS, and Joel Rosenbaum, PhD, at Yale University, started with basic research on cilia of the tiny green alga Chlamydomonas.  In the process of studying the components of the algal cilia, Pazour and colleagues found that a protein necessary for algal ciliary assembly was very closely related to another protein, termed Tg737, associated with polycystic kidney disease in mice.  How defects in the Tg737 protein caused kidney disease was not known until close inspection of the diseased mice by Pazour and colleagues revealed that they were unable to form normal kidney cilia.  This was the first indication of a role for cilia in kidney disease.

“This is a spectacular example of the impact of basic biological research on model organisms to understanding human diseases” commented Thomas Pollard, MD, the Higgins Professor of Molecular, Cellular and Developmental Biology at Yale University and a former president of the American Society for Cell Biology.  “Given that variations in essentially all human genes make some contribution to our risk of disease, and thanks to the fact that all living organisms share common evolutionary origins, much can be learned from model organisms.  In this case, basic work on the assembly of flagella in a green alga set the stage for understanding a relatively common human kidney disease.”

International leaders in the field of cell motility, Pazour and Witman have pioneered the use of Chlamydomonas as a model system to study human diseases involving cilia.  “Scientists studying so-called ‘model organisms’ will be heartened by the paper by Pazour et al.” said Ursula Goodenough, PhD, professor of biology at Washington University in St. Louis and another past president of the American Society of Cell Biology.  “It is this kind of synergy, increasingly likely as we come to realize the genetic and cell-biological relationships between all extant organisms, that underscores how important it is that fundamental research goes hand-in-hand with disease-targeted research.”

Witman came to UMMS from the Worcester Foundation for Biomedical Research  –  where he was director of the Male Fertility Program and principal scientist  –  when the foundation merged with the Medical School in 1997.  Pazour, also from the WFBR, joined UMMS as an instructor in the Department of Cell Biology and later this year will become an assistant professor in the Department of Molecular Medicine.

The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research.  The Medical School attracts more than $131 million in research funding annually, 80 percent of which comes from federal funding sources.  Research funding enables UMMS scientists to explore human disease from the molecular level to large-scale clinical trials.  Basic and clinical research leads to new approaches for diagnosis, treatment and prevention of disease. To learn more about polycystic kidney disease, contact the PKD Foundation at 800-PKD-CURE
(800-753-2873),
  www.pkdcure.org.

 

Contact:
Sandra Gray (508) 856-2000

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