Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human genetic disorders, affecting more than 600,00 Americans. It is characterized by progressive development of liquid-filled cysts and increased cell proliferation in the kidney, often resulting in terminal renal failure. Despite of the discovery that mutations of two polycystin genes PKD1 and PKD2 account for all cases of ADPKD, it remains unclear why. We have uncovered a novel function of polycystin in cell division in fission yeast, that will shed new light on altered cell proliferation observed in ADPKD. We found that fission yeast polycystin Pkd2p localizes to the cell division site to regulate cytokinesis, the last stage of cell division. Here we propose to use this model organism to determine the molecular roles of polycystin in cytokinesis. Our central hypothesis is that Pkd2p regulates both the contractile ring and the calcium signaling during cytokinesis through its activity as an ion channel.
Aim 1 To determine how Pkd2p regulates the contractile ring in cytokinesis. We found that the pkd2 mutation surprisingly leads to abnormal constriction of the ring and a large number of the mutant cells are under osmotic stress. We will first determine whether Pkd2p regulates the turgor pressure. We will then determine how Pkd2p regulates the assembly and the constriction of the contractile ring. We expect to confirm that Pkd2 modulates the assembly of the contractile ring by regulating the cellular osmolality.
Aim 2 To determine how Pkd2p regulates the daughter cell separation in cytokinesis. Our preliminary data showed that Pkd2p plays an essential role in the separation of daughter cells. We propose to determine how Pkd2p regulates the calcium concentration in dividing cells. We will also examine how Pkd2p attenuates an essential signaling pathway that regulates the cell separation. We expect to confirm that Pkd2p regulates the calcium concentration in dividing cells and antagonizes the essential signaling pathway.
Aim 3 To determine how different domains of Pkd2p protein work in cytokinesis. Pkd2p possesses three distinct domains with unknown functions. We propose to determine both localization and function of Pkd2p when these domains are removed individually. We expect to confirm that only two domains of Pkd2p are essential with each playing a separate role in cytokinesis. Despite years of research on polycystins, little is known about its function in cell division. Our surprising observation would provide novel insight into the regulation of cell proliferation by polycystins in the pathogenesis of ADPKD. We will use innovative microscopy method in our study. We propose to strongly promote undergraduate research to benefit the large number of first-generation college students at the University of Toledo and to train them to become immersed in quantitative cell biology research.

Public Health Relevance

Mutations in human polycystins PKD1 and PKD2 lead to a common human genetic disorder, Autosomal Dominant Polycystic Kidney disease (ADPKD) that affects more than 600,000 Americans but the underlying molecular mechanism remains unknown. We found surprisingly that polycystin plays a novel function in fission yeast cell division. We propose to expand on this discovery to determine how yeast Pkd2p regulates cell division that may provide novel insight into the regulation of cell proliferation by polycystins in the pathogenesis of ADPKD.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Gindhart, Joseph G
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University of Toledo
Schools of Arts and Sciences
United States
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