Current funded research

In 2019, we awarded research funding to 11 outstanding PKD researchers. The Research Grant and Fellowship Programs will fund critical research to increase understanding of the genetic and pathological processes involved in PKD and to accelerate the development of potential therapies for PKD patients.

The review process

The Review Committee was comprised of 13 PKDF Scientific Advisory Committee (SAC) members and 11 additional scientists and experts in PKD. Each application was assigned two independent reviewers who ranked the grants from one through nine (one being the strongest), and the process was modeled on the NIH peer-review paradigm.

Rankings were based on:

  • significance to PKD research
  • innovation
  • investigator strengths
  • scientific environment
  • approach.

View more grant and fellowship awardees

2019 research grant awardees

We are excited to share with you the eight grants and three fellowships selected for funding in 2019 below.

2019 Dr. Vincent H. Gattone Research Award


Takamitsu Saigusa, M.D.

University of Alabama at Birmingham

Project Summary

Kidney specific drug delivery using nanoparticles in Pkd1 mice

There is no cure for polycystic kidney disease (PKD), and once kidney damage starts to occur, there is a universal decline in kidney function leading to end stage kidney disease. There are drugs that slows the disease in animal models of PKD but failed to show efficacy in clinical trial such as mTOR inhibitor. One explanation is due to systemic side effects, such as gastrointestinal intolerance, that resulted in non-adherence leading to ineffective treatment. One solution to circumvent the systemic adverse effects is the development of kidney specific drug delivery. This reduces the chance of the drug being taken up by the liver, which is the major source of drug metabolism. The overall goal of this proposal is to utilize kidney targeted nanoparticles to deliver drugs, specifically in mouse models of PKD.

Biography

Dr. Saigusa earned his medical degree from the National Defense Medical College in Japan and completed his clinical training in Internal Medicine and Nephrology in both Japan and in the US. During his Nephrology fellowship training at the Medical University of South Carolina, he began his research in primary cilia and PKD under the mentorship of Dr. P. Darwin Bell. His contribution to the field of PKD research includes studying how loss of cilia or polycystin1 activates the intrarenal renin-angiotensin system that promotes cystogenesis in PKD mice, funded by the NIH/NIDDK K08 award. Dr. Saigusa is currently a physician-scientist at the University of Alabama at Birmingham who sees patients with kidney disease and conducts laboratory research. His current research interest is to determine whether factors that increases kidney size, such as high protein diet, accelerates cyst growth through activating the immune cells in PKD mice.

2019 Young Investigator Award


Sorin Fedeles, Ph.D.

Yale School of Medicine

Project Summary

Controlling the viability of PKD mutant cells via inactivation of XBP1 as a novel strategy to treat ADPKD

Polycystic kidney and liver diseases belong to a family of genetic fibrocystic disorders that primarily affect the kidney and liver. The current proposal focuses on a pathway i.e. Ire1α-XBP1 that we have recently implicated in the pathogenesis of ADPKD and that we have found, to our surprise, to play an important role in controlling the viability of Pkd1 deficient cells. Genetic inhibition of this pathway in relevant mouse models of ADPKD led to a slowing down of disease progression and significantly improved kidney function. Avenues that can inhibit Ire1α-XBP1 may thus hold clear therapeutic potential for the treatment of ADPKD and potentially, ARPKD.

Biography

Sorin Fedeles has an extensive background in academic basic research with a focus on genetic kidney diseases. Through his research he has contributed to the understanding of the genetic and molecular mechanisms of Autosomal Dominant Polycystic Kidney and Liver Disease (ADPKD/ADPLD). He obtained his PhD in Genetics at Yale and after his postdoc continued at Yale as a research faculty. During the last few years, he spearheaded a collaboration with a bio-engineering group at MIT to develop a novel class of drugs for the treatment of ADPKD which has recently secured patent protection through the combined efforts of Yale’s and MIT’s technology licensing teams. Sorin is passionate about scientific innovation and the process required to advance discoveries along the science-business continuum. In order to develop his business knowledge, he pursued an MBA at Yale SOM (class of 2016) and complemented it with a Blavatnik Fellowship in Life Science Entrepreneurship where emerging science and business leaders identify breakthrough innovations emerging from Yale in order to foster their commercialization.

Liudmila Cebotaru, J.D. M.D.

Johns Hopkins University

Project Summary

Small molecule correctors reduce cyst growth in ADPKD

Adult autosomal dominant polycystic kidney disease is characterized by the progressive enlargement of multiple renal cysts, leading to the failure of the kidney to function in 50% of patients. There are currently limited therapies that can alter the progression to renal failure. We provide compelling preliminary data demonstrating that VX-809, a drug in clinical use to treat patients with cystic fibrosis (CF), can reduce cyst growth and improve renal function in an aggressive mouse model of ADPKD. VX-809 reduces cysts via a novel mechanism, and we propose that VX-809 promotes the absorption of fluid from inside the cyst and, at the same time, robs the cysts of their ability to grow. Our objective is to provide proof-of-principle, based upon its mechanism of action, that VX-809 can be used to treat patients with ADPKD.

Biography

Dr. Liudmila Cebotaru’ s training in medicine began at the age of 18, when she received a R.N. degree from Medical College of Balti, Moldova. She continued her medical training by obtaining an M.D. degree from “Carol Davila” University of Medicine and Pharmacy of Bucharest, Romania, and then obtained further training in the areas of pathology. While studying medicine, she also successfully achieved a J.D. degree from the University of Bucharest, Law School and continued in the US, where she later received a Master’s Degree in US Law from the University of Baltimore. Her training in the U.S. began as a post-doctoral fellow at Johns Hopkins University in Gastroenterology and Physiology. She remained at JHU and was promoted to Associate Professor in 2017. In keeping with her training in both medicine and basic science, her passion is to understand the molecular basis of the disease process and to restore normal function to disease-causing mutant proteins. She strongly believes that by understanding the mechanism of the disease process at a basic level, we can devise strategies to correct or at least, bypass defective proteins and restore function. She is currently conducting extensive studies in developing gene therapies for Cystic Fibrosis and in the role of CFTR in PKD. As a result of her past studies on the mechanism of how the cell handles defective proteins and how to rescue function using inhibitors, small molecule potentiators and correctors, she uncovered a new strategy for reducing cyst growth in ADPKD.

Timothy Fields, M.D. Ph.D. and Katherine Swenson-Fields, Ph.D.

University of Kansas Medical Center

Project Summary

Pre-clinical evaluation of Caspase 1 as a therapeutic target in ADPKD

The only drug approved for treatment of ADPKD is tolvaptan, which has side effects that can limit its use. Our goal is to identify new therapies for ADPKD to complement tolvaptan. Our studies have implicated a cellular protein complex called the inflammasome in PKD progression. To test whether the inflammasome can influence PKD, we engineered a mouse model of ADPKD in which the key component of the inflammasome, Caspase 1, is genetically deleted. Remarkably, deletion of Caspase 1 significantly slowed disease progression. We propose to examine the mechanism by which Caspase 1 affects disease. We will also test an inhibitor of Caspase 1, alone and in combination with tolvaptan, in an ADPKD mouse model. This drug, VX-765, has been shown to be well tolerated in human clinical trials for epilepsy, so success in these aims could facilitate rapid advancement to clinical trials for PKD.

Biography

Dr. Timothy Fields earned his B.A. in Biology from the University of Chicago in 1987 and subsequently obtained his MD and PhD degrees from Duke University. After post-graduate and pathology residency training at Duke University, he served on faculty there until 2008, when he moved to the University of Kansas. He is currently a nephropathologist and Professor in the Department of Pathology & Laboratory Medicine at Kansas. He shares a research laboratory in the Jared Grantham Kidney Institute with Dr. Katherine Swenson-Fields, where their work focuses primarily on immune regulation of disease progression in PKD.

Dr. Katherine Swenson-Fields earned her B.S. in Microbiology, as well as her PhD, from the University of Washington in Seattle. She did post-doctoral training at Harvard Medical School, where she also served as Instructor. She subsequently moved to Duke University, where she served on the faculty in Cell Biology until 2008, when she moved to the University of Kansas. She is currently Research Associate Professor in the Department of Anatomy & Cell Biology at Kansas. She shares a research laboratory in the Jared Grantham Kidney Institute with Dr. Timothy Fields, where their work focuses primarily on immune regulation of disease progression in PKD.

Feng Qian, Ph.D.

University of Maryland School of Medicine

Project Summary

Polycystin-1 Cleavage Product P100: Distinctive Topology, Specific Properties, and Polycystin-2-Associated Channel Activity

This proposal will investigate the little understood product of Polycystin-1 (PC1) processing, P100, which we previously discovered to be generated from intact PC1 protein. We have found that P100 is produced much more in cystic kidneys compared to normal kidneys. We suspect that P100 may play a special role in a healthy kidney and its dysregulation may promote the disease progression. Our idea is that P100 may have distinctive features and form a special ion channel complex with PC2. This project will use a multi-disciplinary approach to examine whether P100 has this function and whether ADPKD mutations affect it. By doing so, we will gain critical information about the new component of PC1 protein complex and its function that is important for ADPKD. Accordingly, the present study has the potential for developing new therapeutic strategies targeting the primary defects of ADPKD, and will greatly transform our understanding of the disease.

Biography

Dr. Qian graduated in Biology at the University of Freiburg, Germany. He received his Ph.D. (Dr. rer. nat.) from the Universities of Heidelberg and Freiburg, Germany under the supervision of Professor Dr. Albrecht Sippel, working on genomic organization, splice products and chromosomal localization of the gene family of transcription factor Nuclear Factor One. He did his postdoctoral fellowship in the laboratory of Gregory Germino, M.D. at Johns Hopkins to study polycystic kidney disease, where he discovered molecular interaction between polycystin-1 and -2, and the “two-hit” mechanism of cystogenesis in human ADPKD. Dr. Qian joined the Johns Hopkins University School of Medicine as an Assistant Professor, and moved to University of Maryland School of Medicine as an Associate Professor in 2012. He uses molecular, cellular and animal models to study the function of proteins encoded by genes whose mutations cause human polycystic kidney disease, and to establish a firm mechanistic understanding of the disease process. His laboratory has discovered cis-autoproteolytic cleavage of polycystin-1 at the juxtamembrane GPCR proteolysis site (GPS) motif and established this post-translational modification as a key mechanism that controls biogenesis, ciliary trafficking and biology function of the protein.

Ian Smyth, Ph.D.

Monash University, Australia

Project Summary

Investigating a new regulator of cyst development in PKD

Mutations in the genes which cause polycystic kidney disease trigger significant changes in signaling within the cells of the kidney tubules. These alterations likely elicit the shifts in cellular behavior which result in increased cell proliferation and cyst formation. We have identified a gene which is overexpressed in PKD and which – when simultaneously removed in animal models of disease – can almost completely prevent the formation of cysts. In this application we seek to understand how this is achieved, whether it might be employed as a mechanism to prevent the formation and/or progression of cystic disease and to understand how this gene functions in kidney epithelial cells. By advancing our knowledge in this manner we hope to identify opportunities to explore for the development of new PKD therapies.

Biography

Professor Ian Smyth is an NH&MRC Senior Research Fellow at Monash University in Melbourne, Australia. He co-heads the Development and Stem Cells Program at the Monash Biomedicine Institute and is the Deputy Head (Research) of the Department of Anatomy and Developmental Biology. His doctoral studies at the University of Queensland focused on understanding the role of the PATCHED genes in human disease. He then undertook postdoctoral work in Edinburgh, Houston and London using forward genetic screens in mice to identify novel genes involved in skin and kidney development and disease. His group’s work focuses on two specific questions: how development of the fetal renal collecting duct system is impacted by genetic mutation and environmental perturbation and how disruption of signaling in these cells in the adult kidney gives rise to cysts in ciliopathy patients.

Terry Watnick, M.D.

University of Maryland Medical Center

Project Summary

BAC transgenesis to model an aneurysm-associated human mutation in mice

ADPKD is a common form of inherited kidney failure that is associated with a 5-10X increased risk of intracranial aneurysms (ICA, dilatations of blood vessels). This is an important problem because aneurysm rupture can result in significant disability and/or premature death. The risk of ICA clusters in certain ADPKD families suggesting that genetics play an important role. Despite the high percentage of ADPKD families (~25%) reporting a history of ICA, there have been no comprehensive studies of the genetic factors that predispose patients to this complication. Our proposal seeks to address this unmet need by modeling an aneurysm-associated human PKD1 mutation in mice and studying its effects in blood vessels. We expect that a better understanding of how PKD gene mutations result in aneurysms will allow us to develop improved strategies for identifying those patients at highest risk for this potentially catastrophic complication.

Biography

Dr. Terry Watnick is Professor of Medicine in the Division of Nephrology at the University of Maryland School of Medicine in Baltimore. She received her medical degree from The Yale School of Medicine and completed her Internal Medicine training at Yale-New Haven Hospital. She then moved to the Johns Hopkins Hospital where she received Clinical Training in Nephrology. She also completed a research fellowship at Johns Hopkins that was focused on the genetics of autosomal dominant polycystic kidney disease. Dr. Watnick directs an inherited renal disease clinic at the University of Maryland. She has been an investigator in several multicenter Clinical Trials recruiting patients with ADPKD, including TEMPO, REPRISE and TAME. She is the Principal Investigator for NIH funded Baltimore Polycystic Kidney Disease Research and Clinical Core Center.

Jing Zhou, M.D. Ph.D.

Brigham and Women’s Hospital

Project Summary

Elucidating the cystogenic proteome in polycystic kidney disease

ADPKD is characterized by the development of bilateral enlarged epithelial-lined cysts in the kidney, which ultimately leads to renal failure in half of the patients. A number of signaling pathways has been found to be dysregulated in ADPKD. However, how polycystin-1, the product of the ADPKD gene mutated in 85% of patients, modulates these pathways remains elusive. This research will utilize a new global technology to identify the proteins changed in the early stage of cyst formation and linked signaling networks. The work shall provide novel insights into the mechanisms of the disease by using multidisciplinary approaches including biochemistry, bioinformatics, cell biology, genetics, and animal models of the disease. This research will likely identify new drug targets and promote the development of new therapies for polycystic kidney disease.

Biography

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.

2019 fellows

Harini Ramalingam, Ph.D.

University of Texas Southwestern Medical Center

Project Summary

Investigating the m6A RNA Methylation Pathway as a Therapeutic Option for ADPKD Treatment

ADPKD is a genetic disease characterized by the growth of numerous fluid-filled cysts in the kidney. Currently, ADPKD is a leading cause of kidney failure. The goal of my project is to find therapeutic targets that can treat ADPKD. We have identified that a novel biochemical pathway called m6A RNA methylation, is elevated in human ADPKD and multiple mouse models of ADPKD. Through genetic modulation of this pathway, we are able to reduce disease progression in one ADPKD mouse model. Next, my aim is to determine whether this pathway is a common mode of disease pathogenesis in clinically-relevant ADPKD models. Recent evidence shows that m6A RNA methylation affects the abundance of proteins. I will employ a cutting-edge technology called Ribo-seq and bio-informatic tools to identify all the actively processed proteins, which are regulated by this RNA modification pathway and are key players of ADPKD progression.

Biography

I received a Bachelor's degree in Computer Science and a Master's in Biological Sciences from Birla Institute of Technology and Science, India in 2009. I received my doctoral degree from the University of Texas Southwestern Medical Center in 2017. I finished my dissertation studies under the tutelage of Dr. Thomas Carroll. My dissertation title was "Balancing Renewal and Differentiation of Progenitor Cells in the Developing Kidney". I joined Dr. Vishal Patel's lab in 2018 for postdoctoral research training. My research is focused on understanding RNA metabolism in ADPKD progression and kidney development.

Venkata Vivek Reddy Palicharla, Ph.D.

University of Texas Southwestern Medical Center

Project Summary

Role of Tulp3-mediated ciliary protein trafficking in kidney cystogenesis

PKD is characterized by the presence of multiple large cysts in kidneys. These cysts result in an abnormal increase in the size of the kidneys, ultimately leading to kidney failure. Only one drug is available to treat PKD. Therefore, it is important to do more research on PKD to develop better treatment strategies. The first step in this process is to understand how kidney cysts are formed. Cells in kidneys have small appendages called primary cilia which are involved in sensing the environment and regulating multiple cellular functions. Earlier research has implicated the involvement of cilia in PKD pathogenesis. Through our research, we aim to understand how protein transport into and out of the cilia regulates cyst formation and test if any of these processes can be of therapeutic potential.

Biography

Dr. Palicharla is a post-doctoral fellow under the mentorship of Dr. Saikat Mukhopadhyay in the Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX. He is currently working on understanding the role of protein trafficking to primary cilia in polycystic kidney disease. He earned his Ph.D. from Centre for DNA Fingerprinting and Diagnostics (CDFD) (Manipal Academy of Higher Education), India, where he worked on identifying novel cellular roles of non-canonical ubiquitin linkages.

Rebecca Walker, Ph.D.

University of Maryland

Project Summary

Relieving the Stress of PKD: A new role of PKHD1 in detoxification mediated via differential cleavage of the intracellular domain

ARPKD is a severe disease causing cyst-development throughout the kidneys. ARPKD is caused by mutation in the PKHD1 gene. The child mortality rate is high, therefore current treatment focuses on addressing severe symptoms in childhood. Patients surviving the first year of life have poorly functioning kidneys and often require extensive hospital treatment. Our knowledge of mechanisms underlying ARPKD cyst-development is greatly lacking. There is a real need for research to understand the fundamental properties of the proteins and mechanisms underlying ARPKD. Our lab has found a possible link between PKHD1 protein and detoxification of harmful chemicals in the kidney. We believe that PKHD1 protein is processed to produce fragments that move around inside kidney cells and activate pathways which warn the cell of toxins. Success in this investigation will transform our understanding of cyst-development in PKD and provide potential innovative targets for patient treatment.

Biography

Dr. Walker received her Bachelor of Science degree from The University of Leicester in the UK where her love for genetics flourished. She went on to receive her PhD from Oxford University in the UK, performing research which began her career in the field of Polycystic Kidney Disease, under the mentorship of Dr. Dominic Norris. She has undertaken important research discussing the significance of Polycystin 2 localization to cilia, a cellular organelle. Upon moving to the USA, she began her postdoctoral research in the Laboratory of Dr. Feng Qian and has expanded her interest to include investigating ARPKD. She has become intrigued by the mechanisms involved in maintaining a healthy tubule architecture and discovering which of these are disrupted in Polycystic Kidney Disease.

2018 research grant awardees

In 2018, we awarded research grants to 15 outstanding PKD researchers.

Dr. Vincent H. Gattone Research Award


Katharina Hopp, Ph.D.

University of Colorado – Denver

Project Summary

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.

Biography

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.

Yale University

Project Summary

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.

Biography

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

Project Summary

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.

Biography

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.

Northwestern University

Project Summary

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.

Biography

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

Project Summary

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.

Biography

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.

Yale University

Project Summary

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.

Biography

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

Project Summary

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.

Biography

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

Project Summary

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.

Biography

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.

Harvard University

Project Summary

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.

Biography

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.

Garvan Institute

Project Summary

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.

Biography

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

Project Summary

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.

Biography

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.

Children’s Mercy

Project Summary

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.

Biography

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

Project Summary

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.

Biography

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

Project Summary

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.

Biography

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.

Mayo Clinic

Project Summary

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.

Biography

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.

2018 fellows

Bruno Balbo, M.D., Ph.D.

Yale University

Project Summary

Targeting the Cell Cycle as a Potential Treatment for ADPKD: the Role of Cyclin-dependent kinase 1

In this study, we will investigate the biological mechanisms in which an essential cell cycle regulator, the Cyclin dependent kinase 1 (Cdk1), interferes with renal disease progression in PKD models. We will focus on how cyst initiation and progression are affected through the subcellular evaluation of cell cycle markers, expression of regulatory proteins and protein-protein interactions. In addition, we will also test the effectiveness of pharmacologic inhibition of the FoxM1 transcriptional factor, a regulator of Cdk1, on halting disease progression. Elucidating the pathogenic mechanisms that link cell cycle regulation, ciliary abnormalities and disease progression in ADPKD could provide a translational basis for potential clinical studies.

Biography

Dr. Balbo is a nephrologist trained at University of São Paulo, Brazil, where he completed a Ph.D. investigating cardiovascular complications in PKD. In 2017 he moved to the USA to undertake a post-doctoral fellowship under the guidance of Dr. Stefan Somlo at Yale School of Medicine.

Laverne H. Duvall Award


Kai He, Ph.D.

Mayo Clinic

Project Summary

Restoring ciliary level of functional polycystins as a novel therapeutic approach for ADPKD treatment

ADPKD is the most common inherited renal disorders. Polycystin 1 and polycystin 2, encoded by the causal genes PKD1 and PKD2, have been proposed to form a receptor/channel complex on kidney epithelial cilia. Accumulating evidence suggest a link between the level of functional polycystins and disease severity, indicative of a dosage model of cystogenesis. We recently discovered a novel paradigm that axoneme polyglutamylation is essential for the ciliary anchoring of polycystins. In this proposal, we will molecularly dissect the pathways regulating axoneme polyglutamylation and the ciliary localization of polycystins. We will further explore if restoring ciliary polycystins, by genetically or pharmaceutically targeting key regulators in glutamylation machinery, will suppress the development of PKD. An imaging-based high-content screening will be further used to discover more promising hits that could restore ciliary polycystins. Accomplishing this project will significantly advance our understanding of polycystin biology, and providing novel therapeutic avenues for ADPKD.

Biography

I received Doctoral degree from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences in biochemistry and molecular biology in 2016. During my Ph.D. training, I worked on studying the mechanisms of cell death-survival determination and cell differentiation. Particularly, I studied the molecular connection between mitochondrial dysfunction and epithelial-mesenchymal transition (EMT) in cancer progression, and the molecular bases of cell fate determination during TGF--induced simultaneous apoptosis and EMT. I moved to Mayo Clinic in 2016 for postdoctoral research training. My current research direction is focus on cilia signaling and ciliopathies, especially autosomal dominant polycystic kidney disease (ADPKD). I focus on how the PKD proteins and other cilia-related signaling machineries properly localize to cilia to execute the sensory function. My long term research goals are advancing the understanding of cilia biology and further identifying novel therapeutic approach/targets/hits that address unmet clinical needs of ciliopathies patients.

Core Lab Grant Award

The PKD Foundation’s Core Lab grant program is designed to support research facilities, databases and services to benefit the entire PKD research community.

Mayo ADPKD Mutation Database

Mayo Clinic

Project Summary

Mayo ADPKD Mutation Database

In other genetic diseases, such as cystic fibrosis, all patients are routinely molecularly screened so that families know their disease causing mutations. At present this does not happen for ADPKD, partly because the value of the data for diagnostics and prognostics is not generally recognized, and because molecular testing is specialized and expensive due to the complex genomic situation of the PKD1 gene. However, as specialized next generation sequencing panels for ADPKD become available and there is more competition to offer testing, the price of testing is likely to decrease. In addition, the value of the patient knowing their specific mutation is likely to be more widely appreciated as the prognostic value of this data is realized, and genetic data is increasing used to select patients for treatment and clinical trials. In cystic fibrosis, therapies geared to specific mutations are being developed. ADPKD is more complex because of the high level of family specific mutations, but mutation focused treatment strategies are still likely to be tested in this disorder in the next few years. For instance, chaperone treatment may be of value for some missense substitutions and read-through drugs help patients with nonsense mutations, while therapies to overcome splicing defects have also been proposed. Hence, the database will play an increasingly important role as a repository of the accumulating genetic data (paired with clinical and in vitro data), allowing the penetrance of specific mutations to be better determined. In addition, it will function as a source of information about patients that (through their nephrologist) can be selected for treatments and specific clinical trials, including targeting specific mutation groups.

Visit Mayo ADPKD Mutation Database website