Research Awards Recipients

Alport Syndrome (AS) is a hereditary disease of glomerular basement membranes (GBM) linked to mutations in genes coding for different chains of collagen type IV. Although the GBM is primarily composed of laminin and Collagen type IV, the de novo production of the α1 chain of collagen type I (Col I) has been observed in experimental models of AS.

Discoidin domain receptor 1 (DDR1) is a unique receptor tyrosine kinase that is activated by extracellular matrix but that can also be activated by collagen. DDR1 deletion in Col4a3 knockout (KO) mice, a mouse model for AS, improves survival and renal function. Podocytes and their proper interaction with the GBM are crucial to maintain the permeability of the glomerular filtration barrier. Our in vitro and in vivo preliminary data indicate that DDR1 can be activated by collagen I in human podocytes. Furthermore, we demonstrate that Col I-induced or genetic activation of DDR1 causes cellular lipotoxicity, a phenomenon that we recently demonstrated to be a key determinant of podocyte injury in other glomerular diseases. In particular, we show that the uptake of free fatty acids (FFAs) is increased in Col I treated podocytes and requires the activation of DDR1 which will ultimately lead to intracellular lipid accumulation due to increased fatty acid (FA) uptake. This phenomenon is also reflected in Col4a3 KO mice, where increased DDR1 activity in kidney cortexes correlates with blood urine nitrogen (BUN) and is associated with increased lipid deposition and increased expression of scavenger receptor B, cluster of differentiation 36 (CD36), a protein involved in FA uptake, cholesterol absorption and activation of inflammatory pathways. Studies by others have shown that CD36 activation can be blocked by the clinically available compound Ezetimibe.

The goal of this proposal is to demonstrate a novel mechanism of podocyte lipotoxicity in AS that is amenable to therapeutic intervention through a repurposing strategy of Ezetimibe.

We will test the novel hypothesis that DDR1-induced podocyte injury in AS requires CD36 dependent fatty acid and cholesterol uptake and that inhibition of CD36-dependent lipotoxicity with Ezetimibe can prevent the progression of kidney disease in Alport Syndrome.

We will address this hypothesis using a combined in vitro and in vivo approach to investigate the role of DDR1 in lipid induced podocyte damage and to determine if CD36 inhibition can prevent intracellular lipid accumulation and podocyte injury in Col4a3 KO mice.

If our hypothesis is confirmed, repurposing strategies for the use of Ezetimibe to treat patients with AS should be fast and safe, as Ezetimibe is an already FDA-approved drug currently labeled for the treatment of patients with hypercholesterolemia.

Biography

Dr. Fornoni is tenured Professor of Medicine and Molecular and Cellular Pharmacology at the University of Miami Miller School of Medicine. She is the Chief of the Division of Nephrology and Hypertension and serves as Director and Chair of the Peggy and Harold Katz Drug Discovery Center. She is also the Associate Director of the MD PhD program. In 2013 Dr. Fornoni gained experience in drug development as Global Head of Discovery in Cardiovascular and Metabolism at Hoffman-La Roche in Basel. She is currently the Vice-President and Chief Scientific Officer of L&F Health LLC, a small start-up company focused on finding a cure for patients affected by chronic kidney diseases.

As a physician-scientist who has maintained a resolutely focused research program that has provided novel and seminal contributions to our understanding of the pathogenesis of kidney disease, her research has been supported by grants from National Institutes of Health, industry and private foundations. She has received prestigious awards, she is a member of ASCI, she serves on the editorial board of Diabetes and Kidney International, she was visiting professor at more than 50 academic institutions and international meetings worldwide. She serves as grant reviewer for NIH, DOD, ADA, AHA, UK-diabetes and the Italian Ministry of Health. Her contributions have been published in high impact journals: Journal of Clinical Investigation, NEJM, Nature Medicine, Science Translational Medicine, Journal of Biological Chemistry, Diabetes among others. She successfully trained several graduate students and post-doctoral fellows, further supporting her accomplishments, dedication and perseverance, and more importantly her unstinted commitment as a physician-scientist.

Moving forward, her vision is one that brings industry, investors and not for profit organizations around the table with the intent to match science with innovation and patients’ motivation to find a cure for kidney diseases.