2020 research awards

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.

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.

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.

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.

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…).

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.

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.

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.

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.