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Mechanisms of nephron formation and repair
The primary focus of our laboratory is to determine the mechanisms of renal tubule formation and repair. When the kidney is injured following ischemia or toxin exposure, the remaining epithelial cells de-differentiate, spread over the denuded basement membrane, divide, and re-arrange themselves in a specific pattern to regenerate functional tubules. This process requires a complex array of events involving rearrangement of cell shape and regulation of cell-matrix and cell-cell interactions. By examining epithelial cell adhesion, migration, and branching tubulogenesis in response to growth factors such as Hepatocyte Growth Factor and Epidermal Growth Factor, we are determining the intracellular signaling events critical for tubule formation during kidney development and following injury. We have focused these efforts on the role of activation of specific MAPK isoforms as well as the PI 3-kinase in the regulation of cell morphogenesis and cell-matrix interactions.
In addition, we are now examining the role of adult stem cells in the recovery from acute tubular necrosis. We have found that bone marrow contains stem cells that can home to and populate the injured tubule, where they differentiate into tubular epithelial cells. We are presently examining how these cells differentiate into epithelial cells and how they can be mobilized for therapeutic use in cases of acute renal failure. Ultimately, we hope that the knowledge gained from these experiments will provide a much more detailed understanding of the events that promote tubule formation, and allow us to augment kidney tubule repair and prevent long-term scarring following renal injury.
Selected publications: Karihaloo A, Karumanchi S, Barasch J, Jha V, Nickel C, Yang J, Grisaru S, Bush K, Nigam S, Rosenblum N, Sukhatme V, and Cantley LG. Endostatin regulates branching morphogenesis of renal epithelial cells and ureteric bud. Proc.Natl.Acad.Sci., 2001; 98, 12509-12514.
Liu Z-X, Nickel CH, Yu CF, Thomas S, and Cantley LG. Hepatocyte growth factor (HGF) induces ERK-dependent paxillin phosphorylation and regulates paxillin/FAK association. J.Biol.Chem., 2002; 277: 10452-10458.
Nickel C, Benzing T, Sellin L., Gerke P, Schermer B., Karihaloo A., Liu Z-X, Cantley LG, and Walz G. The polycystin-1 C-terminal fragment triggers branching morphogenesis and migration of tubular kidney epithelial cells. J.Clin.Inv., 2002; 109, 481-489.
Yu C.F., Liu Z-X, and Cantley LG. ERK negatively regulates the EGF-mediated interaction of Gab1 and the PI 3-kinase. J.Biol.Chem., 2002; 277: 19382-19388.
Kale S, Karihaloo A, Clark P, Kashgarian M, Krause D, and Cantley LG. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J.Clin.Inv., 2003; 112, 42-49.
Ishibe S., Joly D., Liu Z-X., and Cantley L.G. Phosphorylation-dependent Paxillin-ERK association mediates Hepatocyte Growth Factor-stimulated epithelial morphogenesis. Mol. Cell, 2003; 12, 1275-1285.
Karihaloo A., Kale S., Rosenblum N.D. and Cantley L.G. HGF mediated renal epithelial branching morphogenesis is regulated by Glypican-4 expression. Mol.Cell Biol., 2004; 24, 8745-52.
Ishibe S., Joly D., Liu Z-X, and Cantley L.G. Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. Mol. Cell, 2004; 16, 257-67
Krause D. and Cantley L.G. Bone marrow plasticity revisited: protection or differentiation in the kidney tubule? J. Clin. Invest., 2005; 115, 1705-08.
Karihaloo A., Nickel C., and Cantley L.G. Signals which build a tubule. Nephron Exp. Nephrol. 1005; 100, 340-45.
Gwira J.A., Wei F., Ishibe, S., Ueland J.M., Barasch, J. and Cantley, L.G. Expression of neutrophil gelatinase-associated lipocalin regulates epithelial morphogenesis in vitro. J. Biol. Chem., 2005; 280, 7875-82.
Lloyd.Cantley@yale.edu
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