Developmental & Cell Biology, "Organogenesis"
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 to epithelia and form nephrons; in the absence of the ureteric bud these cells die by apoptosis. Hence, the ureteric bud has been called the inducer of the nephron, but neither its signals nor their cellular targets in the mesenchyme have been known. Further, an unequivocal identification and isolation of an epithelial progenitor is lacking. My long-term goal is to discover the mechanisms that produce nephrons from mesenchymal cells. To do this, I decided to identify ureteric bud factors that regulate the mesenchyme. I produced cell lines from the ureteric bud, and by using freshly isolated mesenchyme to screen proteins, I purified a series of factors that cause growth or cell conversion. One inducer is Leukemia Inhibitory Factor (LIF), an IL-6 type cytokine. LIF is expressed by the ureteric bud and deletion of its receptor hinders kidney development. Thus, LIF is the first authentic and necessary inducer of nephrogenesis. I now propose to identify epithelial precursors in the metanephric mesenchyme. This is possible because after the addition of LIF, nephrons appear from discrete clusters of cells that are visible by low power magnification. The cells that give rise to this phenomenon are easily isolated, permitting lineage, gene expression, and morphologic studies to confirm that they are the progenitors of the nephron. Using these isolated progenitors, we then determine if interaction with the ureteric bud is necessary and sufficient to induce their conversion, or whether other intra-mesenchymal signals are required. In fact, a protein from kidney stroma targets epithelial precursors and permits induction by LIF, and I propose to identify this factor. These proposals fractionate and then reconstitute the metanephric mesenchyme from its components to identify epithelial precursors and show that combinatorial signaling by factors from the ureteric bud and from the stroma are responsible for converting precursor cells to nephrons.
1. Huynh TK, Bateman DA, Parravicini E, Lorenz JM, Nemerofsky SL, Sise ME, Bowman TM, Polesana E, Barasch J
. Reference Values of Urinary Neutrophil Gelatinase-Associated Lipocalin in Very Low Birth Weight Infants. Pediatr Res. 2009 Aug 12. [Epub ahead of print]
2. Paragas N, Nickolas TL, Wyatt C, Forster CS, Sise M, Morgello S, Jagla B, Buchen C, Stella P, Sanna-Cherchi S, Carnevali ML, Mattei S, Bovino A, Argentiero L, Magnano A, Devarajan P, Schmidt-Ott KM, Allegri L, Klotman P, D'Agati V, Gharavi AG, Barasch J
. Urinary NGAL marks cystic disease in HIV-associated nephropathy. J Am Soc Nephrol. 2009 Aug;20(8):1687-92. Epub 2009 Jul 23.
3. Parravicini E, Lorenz JM, Nemerofsky SL, O'Rourke M, Barasch J
, Bateman D. Reference range of urinary neutrophil gelatinase-associated lipocalin in very low-birth-weight infants: preliminary data. Am J Perinatol. 2009 Jun;26(6):437-40. Epub 2009 Mar 4.
4. Li JY, Paragas N, Ned RM, Qiu A, Viltard M, Leete T, Drexler IR, Chen X, Sanna-Cherchi S, Mohammed F, Williams D, Lin CS, Schmidt-Ott KM, Andrews NC, Barasch J
. Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev Cell. 2009 Jan;16(1):35-46.
5. Marlier A, Schmidt-Ott KM, Gallagher AR, Barasch J
, Karihaloo A. Vegf as an epithelial cell morphogen modulates branching morphogenesis of embryonic kidney by directly acting on the ureteric bud. Mech Dev. 2009 Mar-Apr;126(3-4):91-8. Epub 2008 Dec 25.
6. Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Saito Y, Yoshioka T, Ogawa Y, Imamaki H, Kusakabe T, Ebihara K, Omata M, Satoh N, Sugawara A, Barasch J
, Nakao K. Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules, and distal nephrons. Kidney Int. 2009 Feb;75(3):285-94. Epub 2008 Oct 1.
7. Sise ME, Barasch J
, Devarajan P, Nickolas TL. Elevated urine neutrophil gelatinase-associated lipocalin can diagnose acute kidney injury in patients with chronic kidney diseases. Kidney Int. 2009 Jan;75(1):115-6; author reply 116. No abstract available.
8. Schmidt-Ott KM, Barasch J
. WNT/beta-catenin signaling in nephron progenitors and their epithelial progeny. Kidney Int. 2008 Oct;74(8):1004-8. Epub 2008 Jul 16. Review.
9. Nickolas TL, O'Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N, Buchen C, Khan F, Mori K, Giglio J, Devarajan P, Barasch J
. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med. 2008 Jun 3;148(11):810-9.
10. Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, Workman R, Syed H, Ali S, Barasch J
, Devarajan P. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol. 2008 May;3(3):665-73. Epub 2008 Mar 12.
Honors and Awards
BA, Magna cum Laude with High Distinction in Biochemistry; Citation in study of Italian Renaissance Art
Dr. Alfred Steiner Award for Medical Research; Representative of Columbia College of Physicians & Surgeons to Associated Medical Schools Awards Program
"Column-1" pass of doctoral defense; Finalist in Association of Anatomy Chairman, Outstanding Dissertation Award
Public Health Ambulatory Care Award; Louis Gibofsky Memorial Prize
Zambetti Assistant Professor of Medicine
Eastern Hypertension Society Finalist
American Society for Clinical Investigation
cytokine, epithelium, histogenesis, mesenchyme, renal tubule, apoptosis, cell differentiation, connective tissue cell, cytokine receptor, gene expression, leukemia inhibitory factor, transcription factor, embryo /fetus cell culture, laboratory mouse, labor