Lloyd Garnet Cantley MD
C. N. H. Long Professor of Medicine (Nephrology) and Professor of Cellular and Molecular Physiology; Associate Chair, Research
Nephrology; physiology and integrative medical biology; epithelial cell migration and morphogenesis; epithelial cell adhesion; migration; branching tubulogenesis
Our laboratory is interested in defining the signaling 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 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. We have recently found that a major component of the repair process involves the activation of adult stem cells from the bone marrow to the kidney. We are presently pursuing the mechanism of mobilization, targeting, and differentiation of these cells using microarray and in vitro differentiation assays.
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 adult and embryonic stem cells in the recovery from acute tubular necrosis. We have found that bone marrow contains stromal cells that can be activated and participate in the repair process. We are presently examining what factors these cells produce and how these factors regulate the endogenous cell responses. In addition, we are studying the pathways that regulate the differentiation of embryonic stem cells to become renal tubule progenitor cells. 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.