Jonathan M. Barasch, MD, PhD
- Department of Medicine
Division of Nephrology
- Department of Pathology & Cell Biology
- Renal Pathology
- Research Studies
- Renal Failure
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- Associate Professor of Medicine
- Associate Professor of Pathology & Cell Biology
Education And Training
- Columbia University College of Physicians and Surgeons
- Internship: Columbia Presbyterian Medical Center, NY
- Residency: Columbia Presbyterian Medical Center, NY
- Fellowship: Columbia Presbyterian Medical Center, NY
Education & Training
- Department of Medicine
Kidney organogenesis results from an interaction of ureteric bud and metanephric mesenchyme. In the presence of the ureteric bud, mesenchymal cells expand and then convert into epithelia and form nephrons; in the absence of the ureteric bud these cells become apoptotic. These observations led to the proposal that the ureteric bud is the inducer of the nephron.
My long-term goal is to discover the mechanisms that produce the epithelial phenotype during the conversion of mesenchymal cells. We started by identifying factors secreted from the ureteric bud that stimulate the conversion of mesenchyme into epithelia. We produced cell lines from the ureteric bud, and collected the media from approximately 35,000 flasks of cells. The conditioned media was fractionated and each fraction tested on isolated embryonic metanephric mesenchyme. By visualizing the response of the explant, we identified fractions with growth activity and fractions that induced conversion into epithelia, tubules and nephrons.
One of the inductive molecules was Leukemia Inhibitory Factor (LIF), an IL-6 type cytokine. In pure form, LIF induced a single mesenchyme to form >100 tubules. LIF and other newer members of the IL-6 family were expressed by the ureteric bud and deletion of the common receptor for IL-6 cytokines reduced the growth of the kidney. LIF was the first purified inducer of epithelial conversion and nephrogenesis. Our plan is to identify novel IL-6 cytokines in the developing kidney. Remarkably, a soluble IL-6 type receptor called CLF is one of the most abundant proteins at the tips of the ureteric bud but its common partner, CLC is not expressed in the kidney, suggesting that it interacts with a novel member of the family. Our focus is to determine whether CLF is an agonist or an antagonist of renal development and to identify the novel partner.
In addition to the cytokines, we have identified a member of the lipocalin family that induces cell conversion and extensive tubulo- and glomerulogenesis. The protein is called Ngal or lipocalin-2. Ngal is now renamed siderocalin because it binds siderophores expressed by microbes, but potentially also present in the mammalian blood and urine. The inductive activity of siderocalin depended on protein loading with a siderophore, suggesting that siderocalin donates iron to the mesenchyme. The targeting of siderocalin was also unexpected; it was predominantly endocytosed by peripheral cells in the kidney including, but not limited to, renal stromal cells. This contrasts with the pattern of labeling by Fe-transferrin which targeted condensed mesenchyme. The specific targeting of siderocalin indicates a novel receptor in renal stroma. Our goal is to isolate this receptor and to identify the endogenous ligands of siderocalin that enable its inductive activity. These studies are critical because siderocalin is not only expressed in epithelial growth, but it is massively re-expressed by mouse, rat, pig and human kidneys exposed to nephrotoxins or ischemia.
The purification of multiple epithelial inducers allows us to identify the responses of the mesenchyme that are in common to more than a single inductive factor. Using microarray analysis of mesenchymes exposed to inducers we discovered a set of genes that characterizes the common inductive response of metanephric mesenchyme. We expect these genes to represent critical regulators of mesenchymal-to-epithelial conversion and propose to determine the role of these factors in the generation of the epithelial phenotype. Our microarray database provides a detailed coverage of our ongoing large-scale genomic research.
Project Dates: 1-Jan-06 to 30-Nov-15
Project Dates: 1-Sep-12 to 31-May-17
- Schmidt-Ott KM, Yang J, Chen X, Wang H, Paragas N, Mori K, Li JY, Lu B, Costantini F, Schiffer M, Bottinger E, Barasch J. Novel regulators of kidney development from the tips of the ureteric bud. J Am Soc Nephrol. 2005 Jul;16(7):1993-2002
- Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005 Apr 2-8;365(9466):1231-8
- Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, Schmidt-Ott KM, Chen X, Li JY, Weiss S, Mishra J, Cheema FH, Markowitz G, Suganami T, Sawai K, Mukoyama M, Kunis C, D'Agati V, Devarajan P, Barasch J. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest. 2005 Feb 10; 115: 610-621
- Zheng Z, Schmidt-Ott KM, Chua S, Foster KA, Frankel RZ, Pavlidis P, Barasch J, D'Agati VD, Gharavi AG. A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2502-7.
- Hanai JI, Mammoto T, Seth P, Mori K, Karumanchi SA, Barasch J, Sukhatme VP. Lipocalin 2 diminishes invasiveness and metastasis of ras transformed cells. J Biol Chem. 2005 Feb 3
- Gwira JA, Wei F, Ishibe S, Ueland JM, Barasch J, Cantley LG. Expression of Ngal regulates epithelial morphogenesis in vitro. J Biol Chem. 2005 Jan 6
- Barasch J, Mori K. Cell biology: iron thievery. Nature. 2004 Dec 16;432(7019):811-3.
- Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, Barasch J, Devarajan P. Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol. 2004 Dec;15(12):3073-82.
- Li JY, Ram G, Gast K, Chen X, Barasch K, Mori K, Schmidt-Ott K, Wang J, Kuo HC, Savage-Dunn C, Garrick MD, Barasch J. Detection of intracellular iron by its regulatory effect. Am J Physiol Cell Physiol. 2004 Dec;287(6):C1547-59.
- Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P. Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol. 2004 May-Jun;24(3):307-15.
- Mori K, Yang J, Barasch J. Ureteric bud controls multiple steps in the conversion of mesenchyme to epithelia. Semin Cell Dev Biol. 2003 Aug;14(4):209-16.
- Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol. 2003 Oct;14(10):2534-43.
- Yang J, Mori K, Li JY, Barasch J. Iron, lipocalin, and kidney epithelia. Am J Physiol Renal Physiol. 2003 Jul;285(1):F9-18.
- Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J. An iron delivery pathway mediated by a lipocalin. Mol Cell. 2002 Nov;10(5):1045-56.
- Oliver JA, Barasch J, Yang J, Herzlinger D, Al-Awqati Q. Metanephric mesenchyme contains embryonic renal stem cells. Am J Physiol Renal Physiol. 2002 Oct;283(4):F799-809.
- Yang J, Blum A, Novak T, Levinson R, Lai E, Barasch J. An epithelial precursor is regulated by the ureteric bud and by the renal stroma. Dev Biol. 2002 Jun 15;246(2):296-310.
- Karihaloo A, Karumanchi SA, Barasch J, Jha V, Nickel CH, Yang J, Grisaru S, Bush KT, Nigam S, Rosenblum ND, Sukhatme VP, Cantley LG. Endostatin regulates branching morphogenesis of renal epithelial cells and ureteric bud. Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12509-14. Epub 2001 Oct 16.
- Barasch J. Genes and proteins involved in mesenchymal to epithelial transition. Curr Opin Nephrol Hypertens. 2001 May;10(3):429-36. Review.
- Takemura T, Hino S, Kuwajima H, Yanagida H, Okada M, Nagata M, Sasaki S, Barasch J, Harris RC, Yoshioka K. Induction of collecting duct morphogenesis in vitro by heparin-binding epidermal growth factor-like growth factor. J Am Soc Nephrol. 2001 May;12(5):964-72.
- van Adelsberg J, Sehgal S, Kukes A, Brady C, Barasch J, Yang J, Huan Y. Activation of hepatocyte growth factor (HGF) by endogenous HGF activator is required for metanephric kidney morphogenesis in vitro. J Biol Chem. 2001 May 4;276(18):15099-106.
- Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA. Mesenchymal to epithelial conversion in rat metanephros is induced by LIF. Cell. 1999 Nov 12;99(4):377-86.
- Barasch J. FGF-2: specific activity in kidney? Kidney Int. 1999 Sep;56(3):1156-7.
- Barasch J, Yang J, Qiao J, Tempst P, Erdjument-Bromage H, Leung W, Oliver JA. Tissue inhibitor of metalloproteinase-2 stimulates mesenchymal growth and regulates epithelial branching during morphogenesis of the rat metanephros. J Clin Invest. 1999 May;103(9):1299-307.
- Barasch J, Qiao J, McWilliams G, Chen D, Oliver JA, Herzlinger D. Ureteric bud cells secrete multiple factors, including bFGF, which rescue renal progenitors from apoptosis. Am J Physiol. 1997 Nov;273(5 Pt 2):F757-67.
- Sakurai H, Barros EJ, Tsukamoto T, Barasch J, Nigam SK. An in vitro tubulogenesis system using cell lines derived from the embryonic kidney shows dependence on multiple soluble growth factors. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6279-84.
- Goldberg MR, Barasch J, Shifteh A, D'Agati V, Oliver JA, Hu C, al-Awqati Q. Spatial and temporal expression of cell surface molecules during nephrogenesis. Am J Physiol. 1997 Jan;272(1 Pt 2):F79-86.
- Barasch J, Pressler L, Connor J, Malik A. A ureteric bud cell line induces nephrogenesis in two steps by two distinct signals. Am J Physiol. 1996 Jul;271(1 Pt 2):F50-61.