Warren L. Lee
MD, University of Toronto, 1997
PhD, University of Toronto, 2006
Postdoc, Weill Medical College of Cornell University, 2007
|Address||St. Michael's Hospital
LKS, Room 613
Toronto, ON M5B 1W8
Dr. Lee received his M.D. from the University of Toronto and was awarded the Cody Gold Medal. He completed residencies in Internal Medicine, Respirology, and Critical Care Medicine in Toronto. He then undertook research training in the Program in Cell Biology at the Hospital for Sick Children in the laboratory of Dr. Sergio Grinstein, completing a PhD in 2006. This was followed by postdoctoral training in Microbiology and Immunology at Weill Medical College of Cornell University (New York, NY) in the laboratory of Dr. Carl F. Nathan. His research focuses on the mechanisms of endothelial permeability.
The lab is a collegial and enthusiastic environment. Students participate in weekly lab meeting and journal club and acquire analytical and presentation skills. There is also a weekly joint lab meeting among all the labs on the floor, giving the student the opportunity to present their work to (and learn from) a multidisciplinary audience.
Learn more: Lee Lab
Mechanisms of endothelial permeability
Every blood vessel in the body is lined with a specialized layer of polarized cells known as endothelium. An essential function of the endothelial monolayer is the regulation of barrier integrity, which prevents the leakage of plasma and proteins out of the circulation while still permitting the flux of nutrients and immune cells to target tissues.
In principle, permeability of the endothelial monolayer can reflect contributions from leaking between endothelial cells (paracellular leak) and through individual endothelial cells (transcellular leak, or transcytosis). It is widely accepted that paracellular leak predominates during inflammatory states such as sepsis and acute lung injury. Accordingly, by far the majority of research on endothelial permeability has focused on this route of endothelial permeability: the methods of study are relatively straight-forward and there is obvious relevance to human disease. In contrast, the contribution of transcytosis to overall endothelial permeability is relatively obscure, particularly in the setting of inflammation. This is largely due to technical difficulties in distinguishing transcellular permeability from intercellular gaps, particularly in a dynamic and quantifiable way. In addition, endothelial cells grown in culture appear to lose the ability to perform transcytosis as they are passaged. Much of the initial work on transcytosis used electron microscopy of animal tissues, an expensive and often a mostly descriptive endeavour. Transcytosis (at least in the apical to basal direction) is best described for the plasma protein albumin and is mediated by caveolae, small vesicles that bud off from the apical endothelial surface and release their cargo at the basal membrane. This process requires the protein caveolin-1 and the large GTPase dynamin; the latter is thought to mediate the scission of internalized caveolae from the apical plasmalemma.
My lab is interested in both routes of endothelial permeability and how they are related.
We study paracellular leak during inflammation; for instance, using the influenza A virus as a model pathogen, we investigate how the virus induces lung endothelial permeability to cause pulmonary edema, a characteristic clinical feature of severe influenza infections in humans. We have reported effects of the virus on lung endothelial viability and on tight junction integrity; interestingly, at least some of the effect of the virus on endothelial barrier integrity is independent of viral replication and involves degradation of the tight junction constituent claudin-5. It is also worth noting that systemic microvascular permeability (i.e. in all organs) is a feature of sepsis that leads to hypotension, organ edema and potentially multiorgan failure. Remarkably, there are no treatments for microvascular leak so identifying and testing potential endothelial barrier-enhancing compounds is another major area of interest for my lab.
Enhancing lung endothelial barrier integrity as a novel therapy for severe influenza infections
Another area of study in the lab is the contribution of endothelial transcytosis to the overall permeability of the endothelium to macromolecules. For example, the circulating hormone insulin must leave the vascular lumen in order to exert its effects on critical downstream tissues such as fat or muscle. In vitro work and early work in dogs suggested that insulin delivery, which includes crossing the microvascular endothelium, is rate-limiting. Thus, one area of study is insulin transcytosis. We also use similar approaches in the study of atherosclerosis, since the accumulation of LDL cholesterol under the arterial endothelium constitutes the first step in the disease. Using these methods, we have reported an unexpected role for the SR-BI receptor and for ALK1 in LDL transcytosis.
The work in the lab is centred on live cell imaging that is complemented by traditional biochemical and molecular biology approaches.
Awards & Distinctions
2011-2016 — Early Researcher Award
BCH 2024H Studies of tissue barriers: Regulation of phenotype and transport across the epithelium and endothelium
BCH473Y Advanced Research Project in Biochemistry
BCH375H Research Project in Biochemistry
BCH373H Research Project in Biochemistry
View all publications on PubMed
A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis.
Armstrong S, Sugiyama M, Fung YY, Gao Y, Wang C, Levy AS, Azizi P, Roufaiel M, Zhu S-N, Neculai D, Yin C, Bolz S-S, Seidah N, Cybulsky M, Heit B, Lee WL.
Cardiovascular Research 2015 (in press). Read
Clathrin-dependent entry and vesicle-mediated exocytosis define insulin transcytosis across microvascular endothelial cells.
Azizi PM, Zyla RE, Guan S, Wang C, Liu J, Bolz S-S, Heit B, Klip A, Lee WL
Molecular Biology of the Cell 2015 Feb 15;26(4):740-50. doi: 10.1091/mbc.E14-08-1307. Epub 2014 Dec 24. Read
The Tie2-agonist Vasculotide rescues mice from influenza virus infection
Sugiyama MG, Armstrong SM, Wang C, Hwang D, Leong-Poi H, Advani A, Advani S, Szaszi K, Tabuchi A, Kuebler WM, Van Slyke P, Dumont DJ, Lee WL
Scientific Reports 2015| 5:11030 | DOI: 10.1038/srep11030 Read
Influenza primes human lung microvascular endothelium to leak upon exposure to Staphylococcus aureus
Wang C*, Armstrong SM*, Sugiyama MG, Tabuchi A, Krauszman A, Kuebler WM, Mullen B, Advani S, Advani A, Lee WL
American Journal of Respiratory Cell and Molecular Biology (2015), in press.
Influenza Infects Lung Microvascular Endothelium Leading to Microvascular Leak: Role of Apoptosis and Claudin-5.
Armstrong SM, Wang C, Tigdi J, Si X, Dumpit C, Charles S, Gamage A, Moraes, TJ, & Lee WL
Plos One (2012). 7(10):e47323 Read
Co-regulation of transcellular and paracellular leak across microvascular endothelium by dynamin and Rac.
Armstrong SM, Khajoee V, Wang C, Wang T, Tigdi J, Yin J, Kuebler WM, Gillrie M, Davis SP, Ho M, Lee WL
The American Journal of Pathology (2012), 180(3), 1308–23
Broken barriers: a new take on sepsis pathogenesis.
Goldenberg NM, Steinberg BE, Slutsky AS, Lee WL
Science Translational Medicine 2011, 3(88), 88ps25