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12.15.2015

Miller School Researchers Receive NIH Grant to Study Cardiac Complications in Kidney Disease

A cardiorenal research team from the University of Miami Miller School of Medicine has received a $1.9 million five-year grant from the National Institutes of Health to study life-threatening complications for the heart in chronic kidney disease.

Principal investigator Christian Faul, Ph.D., will examine the role of a cell surface protein called fibroblast growth factor receptor 4 (FGFR4) in the development of left ventricular hypertrophy (LVH). LVH is abnormal enlargement of the heart and is found in most patients with late kidney disease. Importantly, LVH is a significant risk factor for the development of heart failure, contributing to high patient mortality.

“The poor outcomes and increasing prevalence of heart failure point to the importance of finding new cellular-based strategies to alleviate the cardiovascular burden of chronic kidney disease,” said Faul, Research Associate Professor in the Division of Nephrology & Hypertension and at the Katz Family Drug Discovery Center. “This grant supports the next stage in our seven years of laboratory studies into why traditional cardiac treatments, such as reducing high blood pressure, do not prevent kidney patients from developing LVH.”

In 2011, Faul and former Miller School researcher Myles Wolf, M.D., now professor of medicine and Director of the Center for Translational Metabolism and Health at the Feinberg School of Medicine at Northwestern University, found that elevated levels of fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone, stimulated the contracting cells of the heart, called myocytes, to become larger, leading to the development of LVH.

Since then, Faul began focusing on understanding how FGF23 affects cardiac myocytes.

“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,” he said. That study, “Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy,” was published October 1 in Cell Metabolism, with Faul as the senior author.

Faul’s new NIH grant aims to bring his cardiac research to the next level, including a more detailed analysis of the structure and function of the heart in animal models with elevated FGF23. Most important, the proposed study will determine if FGFR4 activation in the heart per se is sufficient to induce LVH in rodents.

“It is likely that by studying cardiac effects of FGF23 in animals with kidney injury, we have uncovered a general pro-hypertrophic signaling pathway, and we hypothesize that FGFR4 activation in the myocardium might contribute to LVH in animal models with primary cardiac injury and normal kidney function,” said Faul.

Faul teamed up with Michael S. Kapiloff, M.D., Ph.D., professor of pediatrics and medicine, and Director of the Cardiac Signal Transduction and Cellular Biology Laboratory at the Interdisciplinary Stem Cell Institute (ISCI), who is a co-investigator on the grant. Kapiloff and his laboratory, including Eliana C. Martinez, M.D., Ph.D., research assistant professor of pediatrics, and also of ISCI, will study cardiac structure and function in Faul’s rodent models. They will use echocardiography and other state-of-the-art technologies to study the heart in order to determine the role of FGFR4 in normal mice, and in mice that have been surgically altered to mimic common heart diseases such as hypertension or aortic valve disease.

“I am very excited to work together with Mike on this translational research project,” said Faul. “Having him on the team, with his broad background in molecular cardiology and his expertise in the underlying experimental techniques, especially in regards to in vivo analyses, made this NIH grant application extremely strong and competitive, which has been clearly recognized by the grant reviewers.”

“It is exciting to be working with Christian on this project,” said Kapiloff. “How the heart and kidney interact in disease is an area poorly understood, and this collaborative project should reveal important new insights contributing to our understanding of heart failure. As heart failure is expected to continue to increase in prevalence in the future, we need new ideas for how to treat heart failure and Christian’s research regarding FGFR4 is likely to provide important new clues in this regard.”

Faul’s studies have received support from Alessia Fornoni, M.D., Ph.D., professor of medicine and Director of the Katz Family Drug Discovery Center, Oliver Lenz, M.D., Interim Chief of the Division of Nephrology and Hypertension, Joshua M. Hare, M.D., Louis Lemberg Professor of Medicine and Director of ISCI, and Roy Weiss, M.D., Ph.D., Chairman of the Department of Medicine and the Kathleen & Stanley Glaser Distinguished Chair in Medicine.

Faul is also looking ahead to the possibility of clinical trials.

“Ultimately, we would like to protect the heart by preventing the development of LVH in patients with chronic kidney disease,” he said. “I think that FGFR4 would make a great drug target.”

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