06:29pm Friday 17 January 2020

Nephrology Researcher Identifies Receptor Implicated in Life-Threatening Cardiac Complication

“Our translational study indicates that blocking FGFR4 could be a potential strategy for protecting patients with kidney disease from left ventricular hypertrophy (LVH), dangerous alterations in the structure and function of the heart muscle,” said Christian Faul, Ph.D., research associate professor in the Division of Nephrology and Hypertension and at the Katz Family Drug Discovery Center at the University of Miami Miller School of Medicine.

Faul is senior author of the study, “Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy,’ which takes an innovative multidisciplinary approach to addressing one of the most challenging aspects of understanding pathologies that are associated with chronic kidney disease. The study, published October 1 in Cell Metabolism, was spearheaded by two members of the Faul laboratory, Alexander Grabner, M.D., and Ansel Amaral, M.D., Ph.D., with the help of four graduate students in the lab, Karla Schramm, Saurav Singh, Alexis Sloan, Ph.D., and Christopher Yanucil.

“Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of chronic kidney disease,” said Faul, who has spent the past seven years studying why traditional cardiac strategies such as reducing high blood pressure do not prevent kidney patients from developing LVH.

Since 2008, Faul has worked with former Miller School professor Myles Wolf, M.D., who is currently professor of medicine and director of the Center for Translational Metabolism and Health at the Feinberg School of Medicine at Northwestern University, on research into fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone that is elevated in patients with chronic kidney disease. In a 2011 landmark study published in The Journal of Clinical Investigation — which to date has been cited more than 600 times — the two investigators found that FGF23 is a major risk and causative factor in stimulating myocytes of the heart to become larger, leading to serious cardiac problems and death.

Since then, Faul began focusing on identifying the cell surface receptor and signaling pathways that FGF23 uses to injure cardiac myocytes. “While blocking all four members of the FGF receptor family would de-activate this pathway, this approach also had significant toxic effects,” he said. “Therefore, we designed a series of experiments with the aim to identify the specific FGF receptor isoform, and we looked for tools that would allow us to block this isoform in a more specific and targeted manner. Our biochemical work pointed to FGFR4 as the key target, which we were able to confirm in our cell culture models and eventually in three different animal models.”

Faul said the laboratory study provides the foundation for potential clinical trials in the future, adding, “Ultimately, we would like to protect the heart by preventing the development of LVH in patients with chronic kidney disease.”

“I am most proud of the true collaborative and translational nature of this study involving researchers from different scientific disciplines and continents,” said Faul. Because the role of FGF receptors has been studied by cancer researchers, Faul reached out to a renowned expert in studying receptor signaling and cancer biology, Axel Ullrich, Ph.D., director of the Department of Molecular Biology at the Max Planck Institute of Biochemistry in Munich, Germany. “Ullrich developed a genetic mouse model where FGFR4 is always switched on,” explained Faul. “In collaboration with his team we detected cardiac injury in these mice, which confirmed our hypothesis and provided a key component for our study, and it opens new avenues for our future research.”

Another key element for the success of this project was Faul’s collaboration with U3 Pharma GmbH, which has developed an antibody that specifically blocks FGFR4, and is now undergoing clinical trials in breast cancer patients. “While the focus of this pharmaceutical company is cancer, they recognized the importance of studying potential effects of their blocking antibody in cardiovascular disease and supported our research,” Faul said. “It was an ideal collaboration, and I think it serves as a great example that successful collaborations between academia and industry are possible and can massively increase the significance of our bench research and provide novel tools for future therapeutic studies in humans.”

“Finally, I am extremely happy and proud that this work has been supported by collaborators and friends from within the Miller School,” Faul said. He acknowledges the laboratory of Lina Shehadeh, Ph.D., assistant professor of medicine, who conducted important experiments to analyze the localization of FGFR4 within the heart. He also thanked Alessia Fornoni, M.D., Ph.D., associate professor of medicine and the Peggy and Harold Katz Family Chair, and Joshua M. Hare, M.D., Director of the Interdisciplinary Stem Cell Institute, both long-time collaborators of Faul.

University of Miami,

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