Karsan, Aly
Associate Professor, Dept of Pathology and Laboratory Medicine
M.D. (1986) Queen's University
Hematological Pathology Residency (1990-1993), UBC
Research Fellowship (1993-1997), University of Washington
Clinician-Scientist(1997-2003), Canadian Institutes of Health Research
Biomedical Scholar (2002-present), Michael Smith Foundation for Health Research
Website: http://www.bccrc.ca/mb/people_akarsan.html
Research Interests
Our research centres around understanding the biology of endothelial cells. Within this large area we have three main areas of interest: 1) To understand the mechanisms of angiogenesis in cancer and ischemia; 2) To understand the molecular mechanisms of endothelial apoptosis; and 3) To determine the mechanisms of endothelial differentiation from bone marrow precursor cells. In all projects we are using molecular and cell biology techniques and in vivo models, and more recently proteomic approaches.
The first major interest of my lab deals with the mechanisms of angiogenesis. The development of new vessels is essential in several physiological and pathological situations. In particular, the growth and spread of cancer requires that new blood vessels incorporate into the tumor. These new blood vessels provide nourishment for growth growth of the tumor as well as a channel for the distant migration of tumor cells (metastasis). The lab is currently studying the role of a family of transmembrane receptors called Notch in angiogenesis and apoptosis. We have also begun investigating the role of Notch signaling during a transdifferentiation process, referred to as endothelial-to-mesenchymal transformation, which is required for proper heart development.
The second area pursued in my lab follows on the observation that lipopolysaccharide (LPS, bacterial endotoxin) and inflammatory cytokines paradoxically activate death (apoptosis) and anti-death pathways in endothelial cells. The net effect is that these inflammatory mediators, in general, alter endothelial function, but do not kill the cell. However, in certain situations the death pathway can overwhelm the survival signals resulting in endothelial death. The sequelae of endothelial death are variable, but can be summarized as enhancing the proinflammatory and procoagulant effects of inflammation. This "excessive" inflammation can be catastrophic resulting in clinical syndromes such as: adult respiratory distress syndrome, rejection of transplanted organs and exacerbation of autoimmune disorders such as scleroderma. Studies from our lab and others indicate that the anti-apoptotic effects of LPS are signaled through different mechanisms from tumor necrosis factor, an inflammatory mediator important in sepsis. Current studies focus on elucidating the LPS-initiated cell survival and apoptotic pathways.
Finally, it has been demonstrated that in the adult new endothelial cells can differentiate from precursor cells that are present in the bone marrow. However, the molecular mechanism for these cells to become endothelial rather than blood cells is not known. We are in the process of trying to understand these mechanisms, to determine whether we can use these cells to target angiogenic areas of tumors.
Selected Publications
KG Leong, X Hu, L Li, M Noseda, B Larrivee, C Hull, L Hood, F Wong, A Karsan: Activation of Notch4 inhibits endothelial sprouting by promoting b1 integrin-mediated adhesion. Mol Cell Biol 22:2830-41, 2002.
C Hull, G McLean, F Wong, PJ Duriez, A Karsan: Lipopolysaccharide signals an endothelial apoptosis pathway through TRAF6-mediated activation of c-Jun NH2-terminal kinase. J Immunol 169:2611-8, 2002.
B Larrivee, DR Lane, I Pollet, PL Olive, RK Humphries, A Karsan: VEGFR-2 induces survival of hematopoietic progenitors. J Biol Chem 278:22006-13, 2003.
I Pollet, CJ Opina, C Zimmerman, KG Leong, F Wong, A Karsan: Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-kB and c-Jun N-terminal kinase. Blood 102:1740-2, 2003.
F MacKenzie, P Duriez, F Wong, M Noseda, A Karsan: Notch4 inhibits endothelial apoptosis via RBP-Jkappa -dependent and -independent pathways. J Biol Chem 2003 Dec 29 [Epub ahead of print].
F Wong, C Hull, R Zhande, J Law, A Karsan: Lipopolysaccharide initiates a TRAF6-mediated endothelial survival signal. Blood (In press, 2004).
M Noseda, G McLean, K Niessen, L Chang, I Pollet, R Montpetit, R Shahidi, K Dorovini-Zis, L Li, B Beckstead, RE