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Dr. Vincent H. Gattone Research Award
Katharina Hopp, Ph.D.
University of Colorado – Denver
Understanding the role of CD8+ T-cells in halting renal cystogenesis
To date research on therapeutics for polycystic kidney disease (PKD) has primarily focused on disrupted pathways in the cystic kidney tubule. However, recent studies in other fields, such as cancer, have shown that cancer cells communicate with their surroundings, and that targeting these communications can alleviate disease. One important cell type within cancers or the cystic kidney surroundings is immune cells. This proposal focuses on a specific immune cell type, T-cells, which we have shown play an important role in keeping cyst growth at bay. Expanding on this observation, we now are examining how T-cells communicate with the cystic tubule and whether targeting this interaction provides a novel therapeutic approach for PKD.
Dr. Zhou has a broad background in kidney pathobiology and molecular genetics, with specific training and expertise in inherited kidney diseases. Research in her lab, starting in 1993 at Brigham and Women’s Hospital, Harvard Medical School, centers on the understanding of disease mechanisms for inherited kidney diseases, particularly Alport syndrome and autosomal dominant polycystic kidney disease. For the past 20 years, Dr. Zhou’s lab has made multiple significant contributions to the understanding of polycystin functions and disease mechanisms using multidisciplinary approaches including molecular genetics, molecular and cellular biology, physiology and pathophysiology. As PI of several NIH-funded grants, she laid the groundwork for the proposed research by developing animal models including the first knockout mouse model for polycystic kidney disease and using these models to understand the pathogenesis of the disease.
Whitney Besse, M.D.
Genetic approach to define mediators of polycystin-1 function in polycystic kidney disease
We seek to learn how to compensate for the genetic defect in ADPKD by either increasing the functional amount of the missing proteins or blocking the effects resulting from loss of the mutant proteins. Besides PKD1 and PKD2, many additional human genes are required for the function of the ADPKD proteins. Mutations in these gene can be rare causes of kidney/liver cysts, and study of them can shed light on the pathways we need to target for treatment. This proposal will investigate two such genes, DNAJB11 and PKHD1, in which we identified mutations causing liver/kidney cysts in adults. Excitingly, DNAJB11 is known to have chaperonea function, something that has been upregulated successfully in cystic fibrosis treatment. PKHD1 is the disease gene for ARPKD. We will use mouse models to investigate whether the cysts we see in some carrier parents of ARPKD children suggest that PKHD1 also affects the ADPKD proteins.
Dr. Besse received her Bachelor of Science degree from Brown University, and medical degree from the University of Connecticut School of Medicine. She obtained her clinical training in both Internal Medicine and Nephrology at the Yale School of Medicine. She began her research in polycystic kidney and liver disease under the mentorship of Dr. Stefan Somlo at Yale. She has made important contributions to the field of PKD research by using genetic approaches to identify novel disease genes for isolated polycystic liver disease and unsolved cases of ADPKD. Through biological investigation of her findings, she has described components in the maturation pathway of the ADPKD polycystin proteins.
Alessandra Boletta, Ph.D.
San Raffaele Scientific Institute
Investigating the Role of Mitochondrial Fitness in Polycystic Kidney Disease Progression
ADPKD is a slowly progressive disease, affecting approximately 1/2000 individuals worldwide. Formation and expansion of cysts in both kidneys is the hallmark of the disease. Several pathways de-regulated in the disease offering important therapeutic opportunities. Among these, we and others have reported a dysfunction in basic metabolic needs of the cell, such as glucose utilization and energy production. In preliminary studies we now found that the subcellular organelle deputed to energy production in the cell, the mitochondrion, is structurally and functionally altered. These alterations might explain the metabolic derangement observed. We aim at investigating the structural, functional and molecular details of mitochondrial alterations in the disease. Furthermore, we propose to genetically manipulate the function of mitochondria in animal models to determine whether disease initiation or progression depend on the function of this organelle.
Dr. Boletta graduated in Biology at the University of Pavia, Italy. She carried out her Ph.D.-equivalent training at the Mario Negri Institute in Bergamo, Italy working on gene delivery to the kidney prior to moving to the Johns Hopkins University, Baltimore, MD for her post-doctoral training. Here, she started her scientific activity on Polycystic Kidney Disease, by working on heterologous expression of Polycystin-1 aimed at establishing cellular models to investigate its function.
Dr. Boletta moved back to Italy to establish her independent lab at the San Raffaele Scientific Institute in Milan, where today she is Head of Research Unit and Director of the Division of Genetics and Cell Biology. She uses cellular and animal models to study the pathophysiology of ADPKD. Her laboratory has identified metabolic reprogramming as an important feature of the disease, offering several new options for therapy and novel insights into the pathogenesis of ADPKD.
Paul DeCaen, Ph.D.
The molecular and mechanistic impacts of Finger 1 variants on PKD2 ion channel function in the primary cilia
Many patients with ADPKD inherit and acquire subtle mutations in the PKD2 gene, which encodes for an ion channel — a pore that controls the flow of ions across cell membranes. Yet we still do not know how mutations impact PKD2’s function because it is found in a tiny, hair-like cellular organelle called the “primary cilia,” which presents a significant challenge to study. However, our laboratory has developed state-of-the-art methodologies to assess PKD2 mutations directly from the primary cilia and their impacts on its molecular structure. Here we focus on a cluster of mutations found within Finger 1 of PKD2 and ask how do they alter this channels function and its atomic assembly in the cilia? Understanding the consequences of these mutations is the first step in establishing PKD2 as potential drug target for ADPKD intervention and forms the molecular basis for the initiation of cyst formation in this common disease.
Dr. DeCaen earned a bachelor’s degree in Physiology from the University of California, Santa Barbara and worked as an Associate Scientist for Pfizer Research and development for five years prior to earning his Ph.D. in Pharmacology from the University of Washington. Here, he received his training in ion channel biophysics from Dr. William Catterall. Dr. DeCaen received additional training as a postdoctoral fellow at Harvard Medical School under Dr. David Clapham while investigating the impact of TRP channels on cell physiology. He is a Gottschalk Research Scholar and has published more than twenty publications in journals such as Nature, PNAS, Cell, eLife and EMBO. He is currently an assistant professor at Northwestern University where his lab is focused on the molecular biophysics of Polycystin channels and their signaling from the primary cilia to the cell.
Daria Ilatovskaya, Ph.D.
Medical University of South Carolina
Effects of dietary salt restriction on cystogenesis in ARPKD
Autosomal recessive form of the polycystic kidney disease (ARPKD) is a genetic disorder that has an incidence of 1 in 20,000 live births; infants affected with this disorder, if they survive, develop chronic kidney failure by adolescence and eventually require kidney transplantation. ARPKD patients are advised to limit their salt intake as it is generally accepted that excessive salt consumption is harmful to people with hypertension and chronic kidney disease (CKD). However, latest data show that both excessive and insufficient salt intake might be detrimental for CKD. Currently there are no studies that would address how salt might affect ARPKD development and whether it may produce beneficial or harmful effects. This project is focused on the role of diet, and specifically its salt content, in the development of ARPKD. Anticipated results of this study will provide novel insights potentially useful for the treatment of the disease.
Dr. Daria Ilatovskaya is an early career investigator who has recently started an independent laboratory at the Division of Nephrology at the Medical University of South Carolina (MUSC). She moved to MUSC from the Medical College of Wisconsin (Department of Physiology) after postdoctoral training and early faculty years under mentorship of Prof. Alexander Staruschenko. Dr. Ilatovskaya studies the regulation of ion channels and transporters in polycystic kidney disease and hypertension; her current research is funded by the NIDDK K99/R00 Career Development Award devoted to the role of ATP in autosomal recessive PKD development. Dr. Ilatovskaya has a long-term interest in PKD, and seeks to decipher molecular mechanisms that underlie these complex hereditary conditions in order to pave the road to the cure using basic science tools and models. Dr. Ilatovskaya is a passionate research advocate and an active member of professional societies, where she is working on supporting young investigators and trainees, and promoting kidney disease research.
Karel Liem, M.D., Ph.D.
Role of interstitial cells in renal cystogenesis
Cystic Renal diseases are among the most common human genetic diseases and are associated with the formation of fluid-filled renal cysts composed of epithelial cells, that compromise kidney function. These forms of renal diseases affect both children and adults and is the leading genetic cause end stage kidney disease and is thus a major public health challenge. We have identified a different population of kidney cells, the interstitial cells, that is involved with the initiation/progression of the disease and propose experiments to better understand the cellular and molecular processes by which cysts develop. There is currently no effective pharmacological treatment for cystic diseases and these studies will identify the molecular and cellular signaling pathways associated with initiation of the disease, which will may lead to identifying possible therapeutic targets.
Karel F. Liem Jr. is a developmental biologist. He graduated from Harvard College with a B.A. in Biology and obtained the MD and PhD degrees from Columbia University College of Physicians and Surgeons. He has trained at the Sloan Kettering Institute, University College London and Harvard University. He is currently an Assistant Professor at Yale School of Medicine. The Liem lab uses genetic techniques in the mouse to identify genes and molecular pathways important for embryonic development and disease.
Robin Maser, Ph.D.
University of Kansas Medical Center
Mechanism of polycystin-1-regulated G protein signaling and its role in the pathogenesis and treatment of PKD
Polycystin-1 is the protein encoded by the PKD1 gene, which is responsible for the vast majority of cases of ADPKD. Polycystin-1 is a very large and complex, and is thought to perform multiple cellular functions. Recent studies have demonstrated that the modulation of cellular signaling by polycystin-1 is critical for the prevention of cystic kidney disease. However, essentially nothing is known about how this function of polycystin-1 is regulated. A number of striking similarities, both structural and functional, are shared by polycystin-1 and a group of signaling proteins called the Adhesion class of G protein-coupled receptors (GPCRs). Importantly, mechanisms that regulate signaling by the Adhesion GPCRs were recently elucidated. Our preliminary studies support the hypothesis that similar mechanisms may regulate polycystin-1 signaling. This application intends to build on our hypothesis, which if shown to be correct, will likely lead to new therapeutic approaches for the treatment of ADPKD.
Robin Maser, Ph.D., received her doctorate from the Department of Biochemistry and Molecular Biology at The University of Kansas Medical Center (KUMC) working on the transcription and function of small nuclear RNAs. She pursued postdoctoral studies under the direction of James Calvet, also at KUMC, which focused on identifying genes that were differentially expressed in cystic kidneys of the cpk mouse model of PKD. She later joined the faculty at KUMC and continued to work on multiple aspects of cystic kidney disease, including the signaling functions of polycystin-1, and the pathogenic mechanisms and treatment of ADPKD in collaboration with James Calvet, Jared Grantham, and Vince Gattone, respectively. Research from her lab demonstrated the membrane-embedded structure and biogenesis of polycystin-1. The current project is focused on understanding the mechanism of polycystin-1 regulated G protein signaling and its potential for therapeutic targeting. When not working in the lab, Robin enjoys kayaking, pickleball, woodworking, and spending time with her furry ‘kids’ (2 labrador retrievers).
Jeremy Reiter, M.D., Ph.D.
University of California, San Francisco
Understanding how the ciliary transition zone controls Polycystin-2 localization to cilia
Primary cilia are small projections found on many human cells involved in receiving and interpreting signals from other cells. The products of both of the genes mutated in polycystic kidney disease, called PKD1 and PKD2, localize to the primary cilia of kidney cells. Disruption of ciliary signaling by PKD2 contributes to polycystic kidney disease and disruption of the ciliary gate, called the transition zone, causes a related cystic disorder called nephronophthisis. We will investigate how the transition zone controls the localization of PKD2 to cilia to provide a mechanistic understanding of how defects in the transition zone and PKD2 function cause kidney cysts.
Dr. Jeremy Reiter, MD, PhD, did his thesis work at UCSF with Dr. Didier Stainier, with whom he identified genetic regulators of zebrafish heart and gut development. He did a postdoc with Dr. Bill Skarnes at UC Berkeley, developing gene editing technology to explore mammalian development. The work from the Reiter lab has contributed to the understanding of primary cilia, small antennae-like structures present on almost all human cell types, as sensors of diverse cues. Their work has also shown that cancer cells can be ciliated and addicted to their cilia for uncontrolled proliferation. More recently, the Reiter lab has illuminated how the lipid and protein composition of the cilium is generated to allow it to function as a specialized signaling organelle, and some of the ways in which altering ciliary function causes diseases as diverse as neural tube birth defects and polycystic kidney disease. He currently serves as chairman of the Department of Biochemistry and Biophysics at UCSF.
Adrian Salic, Ph.D.
Taking PKD out of the kidney: dissection of polycystin signaling in a novel cell-based system
Polycystic kidney disease (PKD) is the most frequent life-threatening genetic disease, estimated to affect close to 1 million people in the US alone; currently without remedy, this represents a very large unmet medical need. PKD is caused by mutations affecting either of two proteins, PKD1 and PKD2, which are critical for normal kidney development and function. Our ability to find an effective cure for PKD is hampered by our poor understanding of how PKD1 and PKD2 function in cells, both in the normal kidney and in disease. Recently, we have developed a rapid and robust cell-based system for analyzing PKD1 and PKD2, in a manner not possible using more complicated animal models. We propose to use this powerful novel system to elucidate the molecular mechanisms underlying the function of PKD1 and PKD2, and to identify unknown cellular proteins that cooperate with PKD1 and PKD2.
Adrian Salic is Professor of Cell Biology at Harvard Medical School. His lab focuses on two main directions: (1) Understanding the molecular mechanisms involved in cell-cell signaling through the various pathways critical during embryonic development and in disease; and (2) Developing novel chemical probes for microscopic imaging and functional assays of various biological molecules (nucleic acids, proteins, lipids), in cells and in animals.
John Shine, Ph.D.
Understanding the role of somatic variation and novel mutational mechanisms in the genetic pathogenesis of PKD
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic kidney disorder it causes cysts to develop within the kidney, which eventually destroy the normal kidney tissue and lead to renal failure in many patients. Despite how common the disease is there are still many gaps in our understanding. There are still many families in which we cannot identify the genetic cause of their disease and there remain many questions about the reason kidney cysts develop and destroy the kidney. Our project will use the latest in genomic sequencing technologies to identify new genetic causes of ADPKD and to try and identify unique mutations in individual kidney cysts that may be causing disease. Understanding these mechanisms will help to develop ways to slow and treat ADPKD.
Professor Shine was Executive Director of the Garvan Institute of Medical Research from 1990 until 2011 and remains at the Institute as an Emeritus Professor. He is also Professor of Medicine and Professor of Molecular Biology at the University of NSW. He was Chairman of the National Health and Medical Research Council from 2003–2006, and is President of the Australian Academy of Science. He is a Companion in the Order of Australia and until 2011 was a Member of the Prime Minister’s Science, Engineering and Innovation Council. In 2010 he received the nation’s highest award for science — the Prime Minister’s Prize for Science.
Oliver Wessely, Ph.D.
Cleveland Clinic/Case Western Reserve University
Regulation of Ciliary G-Protein Signaling by Polycystin-1
Polycystic Kidney Diseases are abundant genetic disorders characterized by the formation of fluid-filled cysts in the kidney. A large percentage of the patients carry mutations in Polycystin-1, a large transmembrane protein with similarities to G-protein-coupled receptors. These cell surface proteins regulates many processes in the body. Preliminary data demonstrate that a part of Polycystin-1 regulates the activity of other G-protein-coupled receptor in the vicinity by competing for shared signaling partners. This project will explore how this crosstalk impacts the function of cilia, small, hair-like organelles, which line the surface of cells and are critically important in Polycystic Kidney Disease. Using tools that allow us to specifically assess and manipulate the processes in the cilia we will investigate the cellular and kidney-wide effects of the crosstalk between Polycystin-1 and other G-protein-coupled receptors. This study will provide new insides into Polycystin-1 and how this can be harnessed for novel therapeutic interventions.
Dr. Oliver Wessely obtained his Ph.D. from the University of Vienna in Austria. After a postdoctoral fellowship at UCLA/HHMI and a faculty position at the LSU Health Sciences Center in New Orleans, he is currently Associate Staff in the Department of Cell Biology in the Lerner Research Institute of Cleveland Clinic. His research is centered on general principles of kidney development and their perturbation during disease formation with a focus on Polycystic Kidney Disease.
Laurel Willig, M.D.
Molecular Characterization of Cyst Formation in a Porcine Model of Early ADPKD
Autosomal dominant polycystic kidney disease (ADPKD), the most common genetic renal disease, leads to progressive renal failure secondary to cyst formation. ADPKD is caused by a change in one copy of one of two polycystin genes. Mechanistic studies into the resultant cyst formation suggest that it requires a lack of functional polycystin protein, either due to an acquired second change in the polycystin genes or an inability to produce enough polycystin protein under stressful cellular conditions. New single cell sequencing technology improves our ability to study molecular mechanisms of cyst formation. However, most animal models used to study early cyst formation do not genetically mimic human ADPKD. We propose to use our novel pig model of ADPKD that genetically mimics human ADPKD and state-of-the-art single cell sequencing technology to study the molecular changes in early cyst formation in order to ultimately identify novel therapeutic targets for early ADPKD.
Dr. Willig is a pediatric nephrologist at Children’s Mercy Hospital-Kansas City. She has a master’s degree in genetic epidemiology. She has a special research interest in genomic applications in clinical medicine. Her work in newborn populations is one of the first reports of rapid whole genome sequencing in acutely ill neonates. She has also done work in renal systems biology in adults with systemic inflammatory response syndrome. She currently is the site principle investigator for the NIH funded grant “Early-Stage Polycystic Kidney Disease Biomarkers Repository Study”. Her current research interests involve examining how genomics and epigenomics influence early cyst initiation in polycystic kidney disease. In addition to her research interests, Dr. Willig is an active clinician educator who has given many educational lectures in the Department of Pediatrics and mentored both nephrology fellows and pediatric residents in research projects. Through her role as the Medical Director of the Center for Pediatric Genomic Medicine (CPGM), she is active in educating hospital staff in genomic applications in their research and organizing the research program of the CPGM.
Owen Woodward, Ph.D.
University of Maryland
Disruption of the Apical Junctional Complex in Cystogenesis and ADPKD
Inheritance of polycystic kidney disease genes causes slow growing kidney cysts with severe consequences for kidney function. Study of disease causation is often obscured by the later stages of a multistage disease process. Here we focus on the first stage of ADPKD, cystogenesis, and propose experiments focused solely on the first protein changes that occur upon acute loss of the PKD2 disease gene and protein product PC2. Using a new ex-vivo 3D culture method to grow epithelial kidney tubes in the lab, we will investigate what happens to the junctions between the cells of the tubes as they transform into cysts with the loss of PKD2. Discovery of the initial steps of cystogenesis after PKD2 loss may illuminate precise drugable targets for the development of future PKD therapeutics.
I was born and grew up in Virginia and graduated from the University of Virginia. I received my PhD from the University of Washington, in Seattle, and did by my post-doctoral Fellowship training in the Department of Physiology at the Johns Hopkins University School of Medicine. I joined the Faculty in Physiology at the University of Maryland School of Medicine in 2015 as an Assistant Professor and soon after joined the Baltimore PKD Research and Clinical Core Center as a Co-Director for the Cell Culture and Engineering Core. The one central theme through my training and current work is a desire to better understand the cell and molecular physiology of epithelial cells, how the various channels and transporters function to determine the physiology of the kidney and, ultimately, individuals. We have used this approach in our work to better understand Polycystic Kidney Disease, focusing on the acute cell biological changes that occur with the loss of the PKD genes in renal epithelia cells during the early stages of cystogenesis. When not thinking about cysts, I enjoy hiking and playing soccer with my family.
Yong Yu, Ph.D.
St. John’s University
The role of polycystin-1 in the polycystin-1/polycystin-2 ion channel complex
ADPKD is caused by mutations in two cell membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). These two proteins form a complex and function together to mediate cell signaling. PC2 is an ion channel protein in the complex which controls the flow of ions across the cell membrane, while the function of PC1 is largely unknown. This study will allow us to achieve a molecular understanding of the role of PC1 in the PC1/PC2 complex and how the function of this complex is regulated.
Dr. Yong Yu received his Ph.D. in Biochemistry and Biophysics from the Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences in 2001. He had his postdoc training first at the Center for Molecular Recognition at Columbia University with Dr. Arthur Karlin, then at the Department of Biological Sciences at Columbia University with Dr. Jian Yang. After working at Columbia University as Associate Research Scientist, he joined St. John’s University as an Assistant Professor in 2012 and was promoted to Associate Professor with tenure in 2016. Dr. Yu’s research has been focused on the molecular mechanism of the assembly and function of the polycystin proteins with combined biochemistry, biophysics, electrophysiology, and crystallography approaches.
Xiaogang Li, Ph.D.
The roles of DNA methylation in autosomal dominant polycystic kidney disease
In this study, we will identify aberrant DNA methylation signatures associated with ADPKD and investigate the functional roles and the underling mechanisms of DNA methyltransferase, DNMT1, in regulating cyst progression, and will test whether de-methylation of hypermethylated DNA mediated by DNMT1 delays cyst growth in vivo. In particular, we will use whole-genome bisulfite sequencing (WGBS) to examine the DNA methylation profiles of normal human and ADPKD kidney samples. We will also identify novel DNMT1 target genes in regulating renal epithelial cell proliferation, apoptosis and ciliopathy during cyst development. Our study will identify the methylation of specific genes in PKD associated signaling pathways and in pathways not previously studied in PKD, which should forward our understanding about the roles of DNA methylation in ADPKD progression. Accomplishing this project will lead to a better understanding of the mechanism of renal cyst formation and will provide novel therapeutic targets for ADPKD treatment.
Xiaogang Li, Ph.D., Professor of Medicine at Mayo Clinic and Honorary Investigator of Mayo Translational PKD Center. He is also a professor of Biochemistry and Molecular Biology at Mayo. His research encompasses both basic science and translational aspects of PKD. In particular, he is widely regarded as one of the world’s foremost authorities on epigenetics and renal inflammation in PKD. Furthermore, he re-evaluates the roles of apoptosis in autosomal dominant PKD, contributing to a better understanding of the mechanisms of this disease. He has published extensively in the field including publications in Nature Cell Biology, Nature Medicine, and Journal of Clinical Investigation. His studies are leading to the use of promising new therapeutic drugs in PKD treatment. In addition, he served as the editor of a book entitled “Polycystic Kidney Disease” (2015), which was the first PKD book on NIH bookshelf.
Last reviewed October 2020