Senger
Donald Senger, Ph.D.
Principal Associate in Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School

330 Brookline Avenue, RN-280E
Boston, MA 02215
Office: 617-667-5766
Fax: 617-667-3591
Email:
dsenger@bidmc.harvard.edu

Education/Training/Appointments:

Donald Senger received a Ph.D. in Biology from the University of Rochester in 1977 and subsequently pursued postdoctoral training at the Center for Cancer Research at the Massachusetts Institute of Technology. He joined the Pathology Department at Beth Israel Deaconess in 1980.


Research Interests: Capillary Morphogenesis

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Basic Research - Our laboratory is focused on defining the signaling pathways that regulate the assembly of endothelial cells into new blood vessels, - a process known as “capillary morphogenesis”. In particular, our recent work has established that defective neovascularization, as it occurs in malignant tumors and other pathologies, is largely due to defective cytoskeleton regulation in the endothelium, resulting in defective capillary morphogenesis. Defective capillary morphogenesis causes formation of architecturally abnormal, poorly integrated blood vessels that leak. These abnormal neovessels fail to conduct blood flow efficiently, resulting in poor perfusion and poor oxygenation of surrounding tissue (hypoxia).


We have identified several key cytoskeleton-signaling molecules that are responsible for defective angio-architecture, vascular leak, and poor integration of new blood vessels. These include GSK-3b, the intracellular protease calpain, and Rho GTPase family members RhoA, Rac1, and Cdc42. With mouse models of VEGF-driven pathological neovascularization in vivo, we have shown that depressed RhoA, Rac1, and Cdc42 activities and, conversely, hyper-activation of GSK-3b and calpain each contribute importantly to the serious vascular defects associated with pathological angiogenesis. In contrast, augmentation of RhoA, Rac1, and Cdc42 activities and modest inhibition of GSK-3b and calpain each improve functional neovascularization, thereby reducing tissue hypoxia. Guided by these findings, our translational goals are to design multi-drug pharmacological strategies for rectifying defects in pathological angiogenesis for purposes of: (1) improving neovascularization, tissue oxygenation, and tissue survival in ischemic vascular diseases, (2) improving efficacy of tumor radiation therapy by reducing tumor hypoxia (radiation cyto-toxicity is oxygen-dependent), and (3) improving tumor perfusion with chemotherapeutic drugs.


New and Noteworthy Publications:

Hoang MV, Nagy JA, Fox JEB, Senger DR. Moderation of calpain activity promotes neovascular integration and lumen formation during VEGF-induced pathological angiogenesis. PLoS ONE 2010, 5(10): e13612. doi:10.1371/journal.pone.0013612. This paper illustrates the importance of calpains in the regulation of neovessel inter-connectivity and identifies moderation of calpain activity as a target for improving neovascular integration and lumen formation.

Hoang MV, Smith LEH, Senger DR. Calpain inhibitors reduce retinal hypoxia in ischemic retinopathy by improving neovascular architecture and functional perfusion. Biochmica et Biophysica Acta Molecular Basis of Disease 2011; 1812: 549-557. This article illustrates that moderate pharmacological inhibition of calpain improves neovascularization, reduces hypoxia, and preserves retina in a mouse model of ischemic retinopathy.

Hoang MV, Nagy JA, Senger DR. Cdc42-mediated inhibition of GSK-3b improves angio-architecture and lumen formation during VEGF-driven pathological angiogenesis. Microvascular Research 2011; 81: 34-43. This paper illustrates the importance of Cdc42 activity and Cdc42-mediated inhibition of GSK-3b for the proper organization of endothelial cells into neovessels with lumens and furthermore identifies Cdc42 and GSK-3b activities as targets for rectifying defective neovascularization.

Hoang MV, Nagy JA, Senger DR. Active Rac1 improves pathological VEGF neovessel architecture and reduces vascular leak: mechanistic similarities with angiopoietin-1. Blood 2011; 117:1751-1760. This report defines the importance of Rac1 activity for proper organization of endothelial cells into neovessels and identifies Rac1 activity as a key target for improving defective capillary morphogenesis and reducing vascular leak.

Senger DR, Davis GE. Angiogenesis; in The Extracellular Matrix, R O Hynes and K M Yamada, editors, Cold Spring Harbor Perspectives in Biology, Cold Spring Harbor Laboratory Press, 2011. This review summarizes the functions of extracellular matrix molecules in regulating angiogenesis.