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| Ashrafi, Kaveh |
| Barber, Diane L |
| Bernstein, Harold S. |
| Black, Brian L |
| Blanc, Paul D |
| Boushey, Homer A |
| Broaddus, V Courtney |
| Brown, James K |
| Caughey, George H |
| Chapman, Harold A |
| Charo, Israel F |
| Chatterjee, Kanu |
| Chuang, Pao-Tien |
| Clyman, Ronald I |
| Conklin, Bruce R |
| Coughlin, Shaun R |
| Derynck, Rik M |
| Dobbs, Leland G |
| Eisner, Mark D |
| Engel, Joanne N |
| Erle, David J |
| Fahy, John Vincent |
| Farese, Robert V |
| Fielding, Christopher J |
| Fielding, Phoebe |
| Fineman, Jeffrey R |
| Glantz, Stanton A |
| Grossman, William |
| Hawgood, Samuel |
| Ingraham, Holly A |
| Jan, Lily Y |
| Kan, Yuet W |
| Kane, John P |
| Kornberg, Thomas B |
| Kurtz, Theodore W |
| Kwok, Pui-Yan |
| Lazarus, Stephen C |
| Malloy, Mary J. |
| Martin, Gail R |
| Matthay, Michael A |
| Mcdonald, Donald M |
| Mikawa, Takashi |
| Minor, Daniel L |
| Mostov, Keith E |
| Nadel, Jay A |
| Ordahl, Charles P |
| Pitas, Robert E |
| Reiter, Jeremy F. |
| Rosen, Steven D |
| Shaw, Robin M. |
| Sheppard, Dean |
| Simpson, Paul C |
| Stainier, Didier Y. R. |
| Wang, Rong |
| Weiner, Orion D |
| Weisgraber, Karl H |
| Weiss, Arthur |
| Weiss, Ethan J |
| Werb, Zena |
| Wiener-Kronish, Jeanine |
| Young, William L |
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CVRI Scientists
Diane L. Barber, Ph.D.
Professor of Cell & Tissue Biology
Research Interests:
Signal transduction and Ion xchangers
Summary:
The research in Diane Barber's laboratory focuses on the regulation and function of two families of plasma membrane ion exchangers, the Na-H exchangers and the Cl-HCO3 exchangers, which regulate intracellular pH. Studies on the regulation of these ion exchangers are designed to investigate the intracellular signaling pathways mediating their activation by hormone and growth factor receptors. Studies on their function are designed to investigate how their regulation of intracellular pH and the actin cytoskeleton contribute to cell growth, differentiation, and migration.
One current emphasis is to map GTPase- and kinase-dependent signaling pathways mediating receptor regulation of plasma membrane ion exchangers. To accomplish this we are using two genetic approaches. The first is to express genetically altered alleles in cells to determine the effects on a particular signaling pathway or cellular response. Using this approach, we determined that the Rho family of GTPases plays a predominant role in mediating activation of ion exchangers by hormone and integrin receptors. We also identified specific Rho-regulated kinases that directly phosphorylate and regulate plasma membrane ion exchangers. The second approach we use relies on interaction cloning strategies to identify protein-protein interactions as a means of determining direct regulators and effectors of ion exchangers. These cloning strategies were used to identify novel kinases and calcium-binding proteins that directly associate with plasma membrane ion exchangers.
A second current emphasis is to characterize the role of Na-H exchangers in GTPase-dependent cell functions such as proliferation, neoplastic transformation, and migration. We determined that Na-H exchangers regulate these cell functions not only through their well-characterized action on intracellular pH homeostasis, but also through a newly identified action on regulating the organization of the actin cytoskeleton. We found that Na-H exchangers play a critical role in mediating cytoskeletal reorganization by integrin receptors and by the Rho family of GTPases, and that they are structurally linked to the actin-based cytoskeleton through a direct association with actin-binding proteins of the protein 4.1 superfamily. Hence, we have identified a novel function of Na-H exchangers in linking the actin cytoskeleton to the plasma membrane. How this novel function contributes to cytoskeletal organization during integrin- and GTPase-dependent cell contractility and migration is currently being determined.
The work in our laboratory is specifically relevant to the CVRI program. We are studying the molecular mechanisms controlling basic cellular processes contributing to cell growth, contractility, and migration. The Na-H exchanger is an important mediator for the inotropic effects of a1-adrenergic agonists, endothelins, and angiotensin II, and its activation is a major mechanism for restoring intracellular pH after acidosis. Influx of extracellular Na+ via this exchanger is a key factor in myocardial pathology associated with ischemia and reperfusion. Additionally, upstream activators of the Na-H exchanger, such as integrins and the GTPase Ga13, regulate the development of the cardiovascular system. Our recent work demonstrating that the Na-H exchanger is critical for cytoskeletal remodeling in response to integrins and Ga13 suggests that its actions on the cytoskeleton may be important for the development and maintenance of cardiovascular functions.
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