Associate Professor, Department of Pathology
Our lab studies lymphocyte migration, with an emphasis on three questions:
Much of our focus has been on how the residence time of T cells in lymphoid organs is determined. We have established that a gradient of the signaling lipid sphingosine 1-phosphate (S1P) is required to guide T cells out of lymphoid organs. We have also identified many of the key cells and enzymes that control this gradient, and we have developed novel tools to map it. Future work will assess how S1P gradients are regulated during an immune response.
With this research, we hope to provide fundamental insight into how lipid gradients are shaped. We also hope that this work will translate to improved therapies for inflammatory disease. Drugs targeting S1P signaling are used clinically as immune suppressants. These drugs block the exit of activated T cells from lymphoid organs, preventing them from reaching organs that are subject to autoimmune attack. They may also have other anti-inflammatory effects. However, because S1P also regulates vascular stability and heart rate, side effects are a serious concern. By determining how S1P gradients are regulated, we may identify targets that enable spatially specific modulation of S1P signaling.
We have also recently turned our attention to the trafficking of transformed T cells through lymphoid organs, using a model of T-cell acute lymphoblastic leukemia (T-ALL). Our first experiments tested the hypothesis that blocking S1P receptor signaling would prevent T-ALL from leaving the lymphoid organs and metastasizing to the brain. This was not the case, however, and it raised the fascinating question of how the migration of leukemic T cells differs from that of normal cells.
We found that, by contrast, loss of signaling through the chemokine receptor CXCR4 after T-ALL onset decimates the leukemia in both murine and human xenograft models of disease—an unexpected result, given that CXCR4 plays relatively subtle roles in normal T-cell development and peripheral T-cell maintenance. Because CXCR4 antagonists are in clinical trials for other cancers, our results may quickly translate to an effective and relatively nontoxic therapy for this aggressive disease.
Our aim for the future is to define additional trafficking requirements for T-ALL, particularly for metastasis to the central nervous system.
PhD from University of California at Berkeley
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