Thrombomodulin, a vascular endothelial sentry

The goal of this project is to explore the diverse vasculoprotective properties of thrombomodulin (TM), an endothelial transmembrane glycoprotein, with recent emphasis on the importance of this molecule in regulating innate immunity in common diseases, including inflammation and tumorigenesis.  Thrombomodulin is ubiquitously expressed in all vascular beds by all vascular endothelial cells.  Via its EGF-like repeats in the central region of the molecule, TM plays a critical role in regulating coagulation, acting as a cofactor in thrombin-mediated activation of protein C, a natural anticoagulant and anti-inflammatory protease.  We have established additionally, that the N-terminal lectin-like domain of TM has direct anti-inflammatory properties, mediated via interactions with mulitple protein partners.  We will continue to characterize these interactions, as they impact on a variety of disease processes, including ischemia-reperfusion injury (renal, myocardial, cerebral), inflammation and tumorigenesis.  In this respect, TM is particularly interesting, as it is also expressed by many tumor cells, and expression levels in most studies are inversely correlated with tumorigenesis and metastasis formation.  Administration of recombinant TM in preclinical studies, has anti-tumor effects, and it is likely that the lectin-like domain of TM exerts this tumor suppressor-like effect.  This hypothesis is being tested, and the molecular mechanisms are being examined.

The perplexing story of the “tumor endothelial marker”, endosialin

The purpose of this project is to evaluate the mechanisms by which the tumor endothelial marker, endosialin (cd248), modulates cell proliferation and contributes to tumorigenesis and inflammation.  Endosialin caught our attention because of its striking similarities to TM. First, the gene encoding both of these endothelial cell receptors are intronless.  Second, the structural domains have similar features.  Notably, both have N-terminal lectin-like domains, and these are almost entirely unique from a structural point of view among the family of C-type lectins, suggesting overlapping functions.  We are therefore examining the structure-function correlates of endosialin, and have already determined, using in vitro and in vivo models, that both the cytoplasmic domain (which has several sites for phosphorylation) and the lectin-like domain, modulate inflammation and tumorigenesis.  Several approaches are being used to determine the underlying molecular mechanisms, and to better characterize the role of these domains, as well as the intact transmembrane protein. Recent findings indicate that endosialin is expressed by pericytes, and its role in that site is also being evlauted. Overall, the physiologic role of endosialin in health and disease – particularly as it pertains to inflammatory disorders and cancer - remains a mystery, and studies are designed to uncover these, in the hopes of identifying novel therapeutic avenues.

Survivin, a cell-survival molecule

This multi-faceted research program evaluates the role of the inhibitor of apoptosis protein (IAP), survivin, in protecting the vasculature, and in transmitting signals to neural progenitor cells to regulate neurogenesis.  Survivin is the smallest member of the IAP family, and has several unique properties in that it inhibits apoptosis, regulates cytokinesis, and promotes the cell cycle.  Multiple splice forms exist, each of which are predicted to have distinct functions and cellular/subcellular distributions. Using mouse models, we have established a critical role of survivin in developmental angiogenesis, that survivin-dependent endothelial cell-derived soluble factors regulate neurogenesis, and also that survivin is essential for migration and proliferation of neural progenitor/stem cells in the brain.  The physiologic significance of these findings in the brain are being examined. We are also examining the role of survivin in protecting against organ transplant rejection. Administration of survivin protects against acute renal failure, and rodent transplant models have been established to evaluate the protective properties of delivering survivin to the donor organ.  These studies, in collaboration with investigators in Brazil, Italy and Spain, are entirely innovative, and are both promising and clinically relevant.

Ed Conway