Lloyd Garnet Cantley MD

C. N. H. Long Professor of Medicine (Nephrology) and Professor of Cellular and Molecular Physiology; Vice Chair, Research

Research Interests

Nephrology; Acute Kidney Injury; Physiology and integrative medical biology; Epithelial cell migration and morphogenesis; Epithelial cell adhesion; Migration; Branching tubulogenesis

Research Summary

Our laboratory is interested in defining the cellular pathways that regulate kidney epithelial development and repair and determining the effector proteins that mediate the actual morphologic changes that occur during tubule formation. We have found that macrophages are critical regulators of both initial injury and subsequent repair, and that cross-talk between macrophages and surviving tubular cells determines the macrophage expression profile that induces tubule repair. We have identified the phosphoinositide 3-kinase and MAPK pathways as critical regulators of epithelial cell migration and morphogenesis and have identified a novel role for ERK at the cell membrane as a key activator of focal adhesion complex turnover.

Extensive Research Description

The primary focus of our laboratory is to determine the mechanisms of renal tubule development 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 examining the role of the innate immune response to kidney injury and found that macrophages home to the injured kidney and initially promote apoptosis of sublethally injured tubular cells. Subsequent macrophage accumulation includes increasing numbers of alternatively activated macrophages that promote the survival and proliferation of the remaining tubular cells to effect tubule repair.

Selected Publications

  • Guo J-K., Shi H., Koraishy F., Marlier A., Ding Z., Shan A., and Cantley L.G. The Terminator mouse: a diphtheria toxin receptor knockin mouse strain for rapid and efficient enrichment of desired cell lineages. Kid. Int., 2013; in press.
  • Schmidt I., Hall I.E., Kale S., Lee S., Lin S.R., He C.H., Lee Y., Chupp G., Moeckel G., Lee C.G., Elias J.A., Parikh C.R., and Cantley L.G. Chitinase 3-like 1 regulates the renal response to ischemic injury and predicts delayed allograft function. J.Am.Soc.Nephol. 2013; 24(2): 309-19.
  • Guo J-K., Marlier A., Shi H., Shan A., Ardito T.A., Du Z-P, Kashgarian M., Krause D.S., Biemesderfer D., and Cantley L.G. Increased tubular proliferation as an adaptive response to glomerular albuminuria. J.Am.Soc.Nephrol. 2012; 23(3):429-437.
  • Lee S., Huen S., Nishio H., Nishio S., Lee H.K., Choi B-S., Ruhrberg C., and Cantley L.G. Kidney injury and repair utilize distinct macrophage phenotypes. J. Am. Soc. Nephrol., 2011; 22(2): 317-326.
  • Hader C., Marlier A., and Cantley L.G. Mesenchymal-Epithelial Transition in epithelial response to injury: the role of Foxc2. Oncogene, 2010; 29:1031-40.
  • Ishibe S, Karihaloo A, Zhang J, Mitobe M, Marlier A, Togawa A, Schmitt R, Czyczk J, Kashgarian M, Geller D, Somlo S, Thorgeirsson SS, Cantley LG. Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology. Development, 136(2):337-345, 2009.
  • Schmitt R, Marlier A, Cantley LG. Increased Zag expression during normal aging suppresses proliferative responses to kidney injury. J Am Soc Nephrol, 19(12):2375-83, 2008.

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