Jonathan Barasch, MD, PhD is a Professor of Medicine, Pathology and Cell Biology. He has been studying the trafficking of iron in kidney development, kidney ischemic damage, and kidney infections.
Dr. Barasch’s lab discovered a switch in iron utilization during late gestation, a receptor for ferritin called Scara5 (Developmental Cell, 2009), a new transmembrane conductance (Unpublished), and with Roland Strong (FHCRC) a siderophore/iron chelator called Siderocalin or Ngal (Molecular CelI, Lancet, Nature Chemical Biology, Nature Medicine).
The mechanisms of iron transport by Siderocalin-Ngal has been a major focus resulting in the identification of a mammalian siderophore (Nature Chemical Biology), an iron chelator therapeutic (a mutant form of Ngal; Unpublished), and a biomarker of tubular damage distinct from volume depletion (Letter to NEJM, Journal Clin Invest, Annals of Internal Medicine, JASN, JACC) now approved for clinical use.
These studies pointed to an unexpected finding, the α-intercalated cell was the critical cellular source of Siderocalin-Ngal. In fact, LPS and Bacteria bound directly to these cells, initiating a cascade that included expression of Siderocalin-Ngal and a myriad of inflammatory cytokines, as well as urinary acidification. Deletion of either Siderocalin-Ngal or the intercalated cells themselves by the deletion of the new transcription factor discovered by Barasch, prolonged bacterial colonization. These data cast a new light on iron trafficking and iron chelation by the kidney as a coordinate program of antimicrobial defense centered on intercalated cells which we propose are new members of the innate immune pathway. Further, we propose that dysfunction of the intercalated cell is a common phenomenon in reflux and obstructive uropathy accounting for changes in urine composition and urine infection.
Dr. Barasch’s current work is focused on modeling iron traffic in kidney damage and kidney infection and on identifying the full functions of intercalated cells. In addition to research, Dr. Barasch sees renal damage patients and teaches molecular sciences at Columbia Physicians and Surgeons, New York.
Ali Gharavi, M.D. is Professor of Medicine and Chief of the Division of Nephrology at Columbia University College of Physicians and Surgeons. His is also the Director of the Columbia Institute of Genomic Medicine initiative for kidney Diseases.
Dr. Gharavi applies state of the art genomics approaches to resolve the pathogenesis of complex traits and through this work he has identified many genes and loci predisposing to glomerulonephritis, hypertension, polycystic liver disease and congenital kidney defects. The ultimate goal of these projects is to reclassify kidney disorders based on their underlying molecular etiology and individualize care for patients with nephropathy. To achieve this goal, he collaborates with many basic and clinical investigators worldwide and has a successful track record of organizing multidisciplinary groups to bring difficult projects to completion.
He is the principal investigator of multiple NIH R01 studies and is also co-Principal Investigator of an NIDDK-sponsored George O’Brien Urology Center (multi-PI with Drs. Mendelsohn and Barasch), aiming to apply a multidisciplinary approach to study the genetic basis of urinary tract defects. Together with Drs. Hripcsak and Weng, Dr. Gharavi also leads the Columbia eMERGE Project, which aims to study implement the return of genetic testing results in electronic health records. Dr. Gharavi’s work has broader implications in Precision Medicine research, and he is now studying the optimal indications for genomic technologies for the diagnosis and targeted care of patients with chronic kidney disease (CKD). Dr. Gharavi’s research program has also served as a vehicle for training of many students, postdoctoral fellows and clinician-scientists, including faculty member who now have independent careers in kidney research. For more information, visit Dr. Gharavi's lab website.
Cathy Mendelsohn, PhD is a Professor of Urological Sciences in the Departments of Urology, Genetics & Development, and Pathology & Cell Biology.
The research in the Mendelsohn lab focused on development of the urinary tract, and identification of progenitors important for urothelial development and homeostasis and cells of origin that contribute to distinct bladder cancer lesions. Her work investigating the cause of obstruction and vesicoureteral reflux using mouse models has led to a deeper understanding of the etiology of theses malformations, which can cause severe kidney disease (Batourina E, et al., Nature Genetics, 2005; Batourina E, et al., Nature Genetics, 2002). Dr. Mendelsohn’s project with the Columbia University O’Brien Center is focused on identification of events and molecular pathways that when abnormal, cause obstruction, including VUR and posterior urethral valves, a rare but serious congenital malformation. She will use mouse models to identify genetic pathways that underlie these abnormalities, which in turn will be used to evaluate mutations in human families with affected individuals, in collaboration with Dr. Gharavi’s group and the Sanna-Cherci group.
Dr. Mendelsohn’s lab has identified adult and embryonic progenitors that generate urothelial cells in the bladder during urinary tract infection and development, respectively (Gandhi et al., Developmental Cell, 2013). An interesting observation from these studies is that retinoids, vitamin A derivatives, are required in progenitor cells in adults, for entry into mitosis. Analysis of gene expression reveals that genes that mediate iron metabolism are dramatically down regulated in mutants with defective retinoid signaling. Dr. Mendelsohn will collaborate with Dr. Barasch looking at the role of iron in regeneration of the urothelium, which may be regulated by retinoid signaling.
The Mendelsohn lab is also interested in identification of progenitors and their associated mutations that drive muscle invasive bladder cancer. Using a mouse model of carcinogenesis together with lineage analysis we find that distinct sub-populations of urothelial cells contribute to distinct types of lesions (Van Batavia et al., Nature Cell Biology, 2014). We are now analyzing lesions produced in our mouse model to evaluate their similarity or differences with respect to human bladder cancer lesions with the goal of obtaining drivers that promote invasion and metastases.