Donald R. Senger, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center


dsenger@bidmc.harvard.edu

Donald R. Senger, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Research Associate, Pathology, Beth Israel Deaconess Medical Center
  • Principal Associate, Pathology, Harvard Medical School

Research Abstract

Our laboratory is focused on defining the signaling pathways and cytoskeletal mechanisms that control the organization of endothelial cells into new blood vessels within tumors, with the overall goal of identifying strategies for alleviating tumor hypoxia that will consequently improve efficacy of oxygen-dependent radio-therapies. We have identified several signaling pathways and associated effector molecules that are critical for normal capillary morphogenesis and, consequently, attractive targets for "normalizing" tumor blood vessels. These include protein kinase A, the GTPases RhoA, Rac1, and Cdc42, and calpains, all of which contribute to endothelial cell cytoskeletal regulation. Guided by this new basic information, we identified a panel of pre-existing drugs as well as natural products that appropriately alter the cytoskeleton-regulating signaling pathways described above and thereby correct architectural and functional defects associated with pathological tumor blood vessels and, furthermore, reduce tumor hypoxia. Currently, we are testing these pharmacological agents and combinations in pre-clinical cancer models for improvement of radiation therapies.

Publications

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  • Senger DR, Davis GE. Angiogenesis. Cold Spring Harb Perspect Biol 2011; 3:a005090. PubMed
  • Hoang MV, Nagy JA, Senger DR. Active Rac1 improves pathologic VEGF neovessel architecture and reduces vascular leak: mechanistic similarities with angiopoietin-1. Blood 2011; 117:1751-60. PubMed
  • Hoang MV, Nagy JA, Senger DR. Cdc42-mediated inhibition of GSK-3硫 improves angio-architecture and lumen formation during VEGF-driven pathological angiogenesis. Microvasc Res 2010. PubMed
  • Hoang MV, Smith LE, Senger DR. Calpain inhibitors reduce retinal hypoxia in ischemic retinopathy by improving neovascular architecture and functional perfusion. Biochim Biophys Acta 2010. PubMed
  • Hoang MV, Smith LE, Senger DR. Moderate GSK-3硫 inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy. Angiogenesis 2010; 13:269-77. PubMed
  • Senger DR. Vascular endothelial growth factor: much more than an angiogenesis factor. Mol Biol Cell 2010; 21:377-9. PubMed
  • Hoang MV, Nagy JA, Fox JE, Senger DR. Moderation of calpain activity promotes neovascular integration and lumen formation during VEGF-induced pathological angiogenesis. PLoS ONE 2010; 5:e13612. PubMed
  • Davis GE, Senger DR. Extracellular matrix mediates a molecular balance between vascular morphogenesis and regression. Curr Opin Hematol 2008; 15:197-203. PubMed
  • Nagy JA, Senger DR. VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype. Exp Cell Res 2005; 312:538-48. PubMed
  • Davis GE, Senger DR. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res 2005; 97:1093-107. PubMed
  • Hoang MV, Senger DR. In vivo and in vitro models of Mammalian angiogenesis. Methods Mol Biol 2004; 294:269-85. PubMed
  • Liu Y, Senger DR. Matrix-specific activation of Src and Rho initiates capillary morphogenesis of endothelial cells. FASEB J 2004; 18:457-68. PubMed
  • Hoang MV, Whelan MC, Senger DR. Rho activity critically and selectively regulates endothelial cell organization during angiogenesis. Proc Natl Acad Sci U S A 2004; 101:1874-9. PubMed
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