Current funded research
In 2020, we awarded research funding to nine 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 the PKDF Scientific Advisory Committee (SAC), additional ad hoc scientists and experts in PKD, as well as a Stakeholder Review Panel made up of PKD patients and caregivers. Each application was assigned three independent reviewers who ranked the grants based on our Guidance for Reviewers that provided separate criteria for scientists and stakeholder.
Rankings were based on:
- significance to PKD research
- investigator strengths
- scientific environment
View more grant and fellowship awardees
2020 research grant awardees
We are excited to share with you the eight grants and one fellowship selected for funding in 2020 below.
2020 Dr. Vincent H. Gattone Research Award
Harrison Kim, Ph.D.
University of Alabama at Birmingham
Developing early prognostic imaging biomarkers of ADPKD based on dynamic changes in cyst growth rates.
Total kidney volume has been used as an indicator of autosomal dominant polycystic kidney disease (ADPKD) severity. However, its accuracy in predicting ADPKD activity may be suboptimal in the early stage of the disease. Also, since total kidney volume increases relatively slowly over time, it may take several years to determine whether ADPKD is favorably responding to therapy. Therefore, we sought an alternative to monitor the early activity of ADPKD. In our initial studies, we tracked the changes in volumes of individual kidney cysts over time and noted that these changes are surprisingly variable between cysts and that they also differ over time. We have developed a new computer software package to monitor these changes. We suggest that the pattern of individual cyst-volume change may serve as a better indicator of early ADPKD activity. We have demonstrated the feasibility of this approach with a small group of ADPKD patients and would like to validate it in a larger population in the proposed study. If successful, this novel approach will improve identification of high-risk ADPKD patients, optimize treatment decisions, and foster development of future therapies for ADPKD.
Harrison Kim is an associate professor in the Department of Radiology for the Division of Advanced Medical Imaging Research at the University of Alabama at Birmingham (UAB). Dr. Kim’s research vision is to globally standardize quantitative imaging of various diseases including polycystic kidney disease (PKD), which will facilitate automatic prognosis and therapy monitoring for patients. Automatic clinical decisions will drastically reduce both the turnaround time and medical expenses for patients. His research mission is to develop hardware and software tools along with this endeavor and validate those tools in multi-institutional clinical trials. In the proposed study, Dr. Kim will develop a novel prognostic imaging biomarker for PKD, which will be used for early therapy adjustment.
Eduardo Chini, M.D., Ph.D.
The Effect of Dietary Methionine Restriction on Pathogenesis of ADPKD and Therapeutic Implication of FGF21 Analogues
Polycystic Kidney Disease (ADPKD) is a common genetic cause of renal failure and is responsible for 5-10% of patients with end stage renal disease (ESRD). The disease is characterized by accumulation of fluid filled kidney cysts that ultimately leads to kidney failure. At present, only FDA approved treatment for ADPKD has relatively moderate effects. Therefore, treatment options for ADPKD patients are largely supportive, including dialysis and renal transplantation. We have previously observed that a decrease in food intake can prevent the development of ADPKD in animal models. Now our preliminary data shows that dietary restriction of single amino acid, methionine has beneficial effects in this cystic disease. We hope that understanding the effects of dietary methionine restriction in ADPKD will lead to the development of effective therapies for this cystic disease.
Dr.Chini is a native from Brazil and has been a clinician investigator at Mayo Clinic for 20 years. His clinical work is focused on the perioperative care of kidney and liver transplant patients. The research in Eduardo Chini laboratory is in the fields of metabolism, nutrition, pharmacology, with implications for cancer, obesity, aging, and kidney disease. In particular, Dr. Chini is interested in metabolism and molecular nutrition. In PKD Dr. Chini’s laboratory was the first one to demonstrate a key role for caloric intake on the pathogenesis of this disease. Furthermore, He and his colleagues have also explore mechanistic implications of caloric restriction in ADPKD and the role of specific macronutrients in this disease. Dr. Chini laboratory is also exploring the nonoxidative and oxidative roles of NAD (as a signaling molecule and energy coin in cells). Dr. Chini’s laboratory has done seminal work on NAD catabolism, including the description of the main enzyme responsible for the degradation of this molecule in mammalian tissues. Dr. Chini is the director of the molecular nutrition platform at the Kogod Center on Aging and director of the mitochondrial research center at Mayo Clinic.
Xiangqin Cui, Ph.D.
Machine Learning for Predicting eGFR Decline in the CRISP Cohort of ADPKD Patients
The rate of disease progression is highly variable among individual ADPKD patients. The recent approval of the first ADPKD therapeutic for patients with a high risk for renal function decline has made identification of such high-risk patients even more critical. Unfortunately, existing models for prediction of renal function decline perform well only in large groups of ADPKD patients, but their accuracy in individual patients is far from optimal. The models developed so far are regression models, which are beneficial for identifying risk factors and providing average renal function decline trajectories for patient subpopulations. However, they are not focused on predicting future renal function in an individual patient. Recently-developed groundbreaking Machine learning/Artificial intelligence (AI) methods are far more patient-oriented and have already transformed the prediction of diverse medical outcomes. Therefore, we propose to develop Machine learning models for predicting renal function in individual ADPKD patients, using the data from one of the best-characterized ADPKD studies (the CRISP study). We will examine various Machine learning methods and compare them with the traditional regression-based methods in prediction accuracy at the individual patient level. We will also test the hypothesis that the contribution of some expensive variables, such as genetic mutations and some advanced imaging data, can be offset by the collection of a large number of routinely obtained clinical variables. We propose to validate the CRISP-based Machine learning prediction models in other cohorts of ADPKD patients, such as the HALT cohort, the Kaiser Permanente cohort, and the VA cohort that we are constructing.
Dr. Cui is currently a Research Associate Professor in the Department of Biostatistics and Bioinformatics at Emory University. Dr. Cui earned her PhD in Genetics from Iowa State University. She was then trained in statistical genetics and bioinformatics at the Jackson Lab as a postdoctoral fellow. In 2004, she joined the Department of Biostatistics at University of Alabama at Birmingham as a faculty member focusing on analytical method development and collaborations in studies employing various high throughput omics technologies. Her interest in PKD research started from mapping modifier genes in mice during her postdoctoral training in collaboration with Dr. Lisa Guay-Woodford and Dr. Michal Mrug. The collaborations continued in the years after she moved to UAB and resulted in multiple publications in PKD basic research. In 2019, Dr. Cui moved to Emory University to lead the Data Analytics Core in the Atlanta VA Medical center and her research focus shifted toward studies based on VA electronic medical records and intervention trials.
Maria Irazabal, M.D..
Role of NOX4, mitochondria and related biomarkers in Autosomal Dominant Polycystic Kidney Disease
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a devastating genetic disorder that causes numerous cysts in the kidneys, and remains a leading cause of renal failure. However, the only FDA-approved therapy for ADPKD (tolvaptan) is limited to slowing-down disease progression, and has associated side effects. Furthermore, the mechanisms that contribute to cyst formation and further damage to the kidney are still uncertain. A better understanding of these processes may assist in development of new therapies with fewer adverse effects and improve the quality of life of these patients.
Another critical problem in the care of patients with ADPKD is that the rate of disease progression varies widely among individuals and markers of renal function don’t change until late stages, representing a major challenge for following these patients, identifying a treatment response or predicting the progression of the disease. Therefore, there is a pressing need for identifying early biomarkers of disease severity/progression and additional targets for therapeutic interventions.
Oxidative stress is the imbalance between the production of harmful free radicals and antioxidants and a major contributor of renal damage in other kidney diseases, but its role in ADPKD is unclear. This proposal will explore for the first time the role of oxidative stress damage in ADPKD and related biomarkers. The findings resulting from this study are likely to have important clinical implications by: advancing the understanding of the mechanisms of renal damage in ADPKD, identifying novel early biomarkers, and highlighting additional processes that could be target for therapeutic intervention.
Dr. Irazabal earned her medical degree from Universidad de la Republica in Montevideo, Uruguay, and completed her research fellowship in renal physiology and polycystic kidney disease at the Mayo Translational PKD Center, Mayo Clinic in Rochester, Minnesota. Her contribution to the field of PKD research includes the development of an imaging classification for autosomal dominant polycystic kidney disease (ADPKD) patients, which is broadly used for selecting which patients with ADPKD to treat. Dr. Irazabal is currently an Assistant Professor and a faculty member at the Mayo Translational PKD Center and her research program focuses on identifying mechanisms contributing to disease severity and progression while identifying early biomarkers in ADPKD. Her research includes in-vitro as well as pre-clinical translational and clinical studies in ADPKD. Specific areas of interest include redox signaling, mitochondrial abnormalities and energetic dysregulations, as well as the contributions of the intra-renal microvasculature to disease severity and progression.
Roman-Ulrich Müller, M.D. and Thomas Weimbs, Ph.D.
University of Cologne and University of California in Santa Barbara
KETO-ADPKD — A pilot trial of ketogenic dietary interventions in ADPKD
Our recent research suggests that simple diets which mimic fasting profoundly inhibit the growth of kidney cysts in animals with PKD. These diets induce the state of “ketosis” that allows fat reserves to be used for energy instead of blood sugar. We discovered that cysts in PKD are unable to adapt, and starve during ketosis. Based on these findings, we propose a clinical trial to test two well-established diets that induce ketosis: (1) fasting and (2) a high-fat/low carb ketogenic diet. ADPKD patients will be treated with either diet for 3 months to find out how well they tolerate these diets, how safe they are and which one is easier to adhere to. The results will be crucial for the design of a subsequent trial to test whether one of these diets slows disease progression in the long-term in a much larger number of ADPKD patients.
Dr. Roman-Ulrich Müller is Vice Director of the Department 2 for Internal Medicine (Renal Unit) at the University Hospital Cologne. He began his medical career at the universities of Freiburg and Heidelberg in Germany. After finishing medical school, Dr. Müller completed his scientific training at Rockefeller University (New York, USA) and Yale University (New Haven, USA). He then returned to Germany to obtain his board certification in Nephrology in the Department of Prof. Benzing at University Hospital Cologne where he now works.
Here, Dr. Müller is head of the ADPKD unit (website) and has established the „AD(H)PKD Registry“, which strives to collect information on the management of ADPKD and has become one of the largest cohorts worldwide. Furthermore, he leads a basic research group that tackles the molecular mechanisms underlying kidney disease, employing modern techniques in molecular biology and biochemistry (website). His special interest is dedicated to renal RNA biology — e.g. RNA-binding proteins and non-coding RNAs — including the discovery of small non-coding RNAs in polycystic disease. Research in Dr. Müller’s laboratory has been funded by grants from federal agencies, including the German Research Foundation and the Ministry of Science North-Rhine Westphalia, by private foundations, including the Marga and Walter Boll Foundation and the German Kidney Foundation, as well as several companies involved in biotechnology and medicine. Based on this work, Dr. Müller is the author of numerous publications on clinical and molecular nephrology in renowned journals.
Whenever this leaves time for other activities, Roman loves to discover the world, no matter whether by campervan, bicycle or — as required by the current pandemic — online.
Thomas Weimbs is a professor at the University of California in Santa Barbara (UCSB) where he directs a research laboratory focused on polycystic kidney disease (PKD). He received his doctoral degree from the University of Cologne, Germany, and then conducted postdoctoral research at the University of California in San Francisco. In 1999, he started his first independent research laboratory at the Lerner Research Institute of the Cleveland Clinic as an assistant professor. There, he started to research PKD after he was approached by a local family affected by PKD who financially supported PKD research in his newly-founded laboratory. Their family foundation still supports PKD research in Dr. Weimbs’ lab today. In 2005, Dr. Weimbs moved his laboratory back to California to join the Department of Molecular, Cellular, and Developmental Biology at UCSB. His laboratory studies molecular mechanisms underlying PKD with an emphasis towards developing new therapies. Research from Dr. Weimbs’ lab has led to a better understanding of PKD and led to novel methods to deliver therapeutics specifically to polycystic kidneys. Some of the most recent research has led to the discovery that commonly available, and safe, dietary supplements can prevent cyst growth in animal models on PKD. Research in Dr. Weimbs’ laboratory has been funded by grants from federal agencies, including the National Institutes of Health and the Department of Defense, by private foundations, including the Lillian Goldman Charitable Trust, the Amy P. Goldman Foundation and the Jarrett Family Fund, as well as several biotech companies. For more information on research in the Weimbs lab, see the website.
In his free time (what free time?), Thomas enjoys playing the saxophone in his jazz band (no, you wouldn’t have heard of them…).
Kristen Nowak, Ph.D.
University of Colorado Anschutz Medical Campus
Adiposity and Time Restricted Feeding in ADPKD
We showed previously that body mass index, determined by a person’s height and weight, is an important predictor of ADPKD progression, even when accounting for other factors. This may be explained by increased fat tissue, which can promote inflammation and other signaling leading to growth of cysts. We would now like determine whether fat tissue in the abdomen may explain this association, by looking at magnetic resonance images (MRIs) that were collected previously. We will also see if weight loss reduces abdominal fat and if this slows kidney growth in adults with ADPKD who are overweight or obese. We will use MRIs from our ongoing weight loss study to answer this question. Changes in metabolism also occur in ADPKD and affect progression. Periods of fasting (restricting the number of hours food is eaten each day, or time restricted feeding) was recently shown to slow ADPKD progression in rodents. We also propose a pilot study of time restricted feeding in adults with ADPKD (limiting intake to 8 hours a day), to ultimately see if this reduces abdominal fat and slows kidney growth. As an important first step, this pilot study will determine if this diet is feasible (whether people can adhere to the diet for one year). Together, these aims will provide a better understanding of the role of fat tissue in ADPKD and whether dietary approaches can slow kidney growth, in part by reducing abdominal fat. These results will provide the foundation for a larger scale trial on this topic.
I am trained as a physiologist with an interest in lifestyle interventions to reduce risk of cardiovascular disease and kidney disease progression. I conduct research on the mechanisms of vascular dysfunction in patients with kidney diseases, including ADPKD, as well as on novel therapeutics to alleviate such dysfunction. I have unique expertise in identifying integrative physiological mechanisms mediating vascular dysfunction, as well as in epidemiology, having recently completed a Master of Public Health. I direct the clinical vascular physiology laboratory for the Division of Renal Diseases and Hypertension. My K01 Career Development Award, sponsored by the National Institutes of Health, is testing the efficacy of curcumin, a naturally occurring polyphenol, in order to improve vascular function and slow kidney growth in children and young adults with ADPKD. I also became recently interested in the role of diet and metabolic dysfunction in ADPKD progression. I have an active NIH R03 grant evaluating the feasibility of two weight loss interventions, daily caloric restriction and intermittent fasting, in adults with ADPKD and overweight or obesity.
Stephen Parnell, Ph.D.
University of Kansas Medical Center
Rescuing Polycystin-1 G-protein Function
The only approved therapy for autosomal dominant polycystic kidney disease (ADPKD) is JYNARQUE, which must be taken long-term and has undesirable side-effects. Most ADPKD cases are caused by mutations in the PKD1 gene, which encodes polycystin-1 (PC1). However, JYNARQUE and other therapies target downstream pathways rather than the primary cause of disease, which is loss of PC1 function.
Prior experiments have shown that restoring PC1 via genetic engineering slows disease in juvenile mouse models. However, it is not known whether this approach will work in adult cystic mice, which are more representative of the human disease condition.
If restoration of PC1 works in both juvenile and adult models of disease, then restoration of PC1 is a potential therapy for PKD. However, genetic restoration of the PKD1 gene is currently not a feasible therapy in humans.
As an alternative to genetic engineering, small portions of the PC1 protein that retain biological activity and can be synthesized in vitro could be developed into a viable therapeutic option. A small peptide from the tail of PC1 contains a biological activity that could potentially copy an essential function of PC1. The hypothesis to be tested is that restoration of PC1 will slow cystic disease progression in adult mice, and that this effect can be copied by therapeutic administration of a synthetically produced, bio-active peptide derived from PC1.
Successful completion of the proposed work would provide a pathway to a deliverable therapy intended to overcome the loss of PC1 function in ADPKD patients.
Dr. Stephen Parnell received his PhD in biochemistry and molecular biology from the University of Kansas Medical Center for his work on the structure and function of the polycystin-1 protein. Following postdoctoral studies on signal transduction at the University of North Carolina – Chapel Hill, Stephen returned to Kansas to apply his new knowledge and skills to the PKD field. As a faculty member within the Jared Grantham Kidney Institute, Stephen’s laboratory utilizes molecular approaches and mouse models of PKD to continue his focus on polycystin-1 function and its role in regulating cellular signaling pathways. Stephen’s passion for PKD research extends beyond the laboratory, as he has numerous family members affected by PKD. The broad, long-term goals of his laboratory are to elucidate the mechanisms of polcystin-1 function in order to develop improved therapies for the benefit of PKD patients.
Christopher Ward, M.D., Ph.D.
University of Kansas Medical Center
Use of exosomal polycystin-1 (PC1) level to diagnose and monitor autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited cause of renal failure affecting 1:800 individuals. At present, there is no biochemical test to diagnose or monitor the disease. Using the finding that small membrane vesicles found in urine (exosomes) contain the protein products of the polycystic kidney disease genes, we have developed a urine based test for ADPKD. The test measures the amount of polycystin-1 in urinary exosomes and can be used to diagnose the disease. The object of this study is to ensure that this test can be used to determine the severity of ADPKD and thus its prognosis. Such a test may be used to make an early diagnosis (as the earlier a treatment is started the better) and to monitor the disease, perhaps as it is being treated. One interesting feature of the PKD1 gene is a large stretch of DNA composed of only two bases as opposed to the usual four. This results in a human gene that does not function as well as the same gene in other animals. When the gene is being copied to RNA, the copying process tends to stop early making a shorter defective form of polycystin-1. There appears to be considerable variation in how much of the full length protein is made by different people. This might be responsible for the variation in the amount of polycystin-1 seen in the urine and in the severity of polycystic kidney disease. We wish to investigate both phenomena in this application.
Dr. Christopher J. Ward was born and raised in Scotland and received his medical training at Edinburgh University qualifying in 1986. He then did a PhD in immunology at the University of Birmingham, England before joining the laboratory of Prof Peter Harris in Oxford. Dr. Ward was closely involved in the positional cloning of the tuberous sclerosis type 2 (TSC2) gene and the polycystic kidney disease type 1 (PKD1) gene and developed a range of antibody reagents designed to detect the product of the PKD1 gene, polycystin-1. In 2000, Drs. Ward and Harris moved to the Mayo Clinic and identified the gene for autosomal recessive polycystic kidney disease (PKHD1) using the pck rat model which is orthologous to PKHD1. Again, Dr. Ward developed antibody reagents to the product of PKHD1, fibrocystin, as well as generating two mouse models of the disease. In collaboration with Dr. Marie Hogan, Dr. Ward showed that extracellular vesicles contain the products of the three major human PKD genes and did an extensive proteomic analysis on these. This survey then lead to the development of a test for ADPKD and to the formulation of the exosome cilium interaction theory (ECIT). This idea suggests that extracellular vesicles, released into the urine flow, can transmit a `urocrine’ signal by interacting with primary cilia and that polycystic kidney disease is due to a failure of this novel signaling pathway.
Laura Onuchic, M.D.
Yale School of Medicine
Polycystic Kidney Disease Proteins and aGPCRs: Elucidating a Novel Signaling Pathway
ADPKD is one of the most common potentially lethal genetic disorders, affecting ~1:1000 individuals. It is characterized by the formation of kidney cysts, whose expansion over time compromises kidney structure and function.
Most ADPKD cases are caused by a genetic mutation in the PKD1 gene, which consequently encodes a defective polycystin-1 protein. The exact mechanisms through which this defective protein leads to disease remain unclear.
The polycystin-1 protein spans the cell membrane and has an intracellular and extracellular portion. We hypothesize that the extracellular portion of the polycystin-1 protein functions as a receptor that regulates intracellular signaling processes. We will study the structural basis for this receptor function and characterize the downstream elements of the cellular signaling machinery that respond to polycystin-1. These studies may illuminate a new biological role for the polycystin-1 protein and shed light on the processes that lead to cyst formation and on potential therapeutic targets.
Dr. Onuchic earned her medical degree from the University of São Paulo, Brazil, where she also completed her residency training as a clinical nephrologist. She moved to the Yale School of Medicine in 2019 to pursue postdoctoral research training under the mentorship of Dr. Michael Caplan, Chair of Cellular and Molecular Physiology.
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
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.
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
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.
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
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.
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
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.
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
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.
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
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.
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
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.
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
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.
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.
Harini Ramalingam, Ph.D.
University of Texas Southwestern Medical Center
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.
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
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.
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
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.
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.
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 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