- Defining the molecular links between coagulation and innate immunity.
Throughout evolution, organisms have developed means to simultaneously contain wounds by limiting bleeding with clot formation and fighting pathogens, thereby enabling rapid healing. Disease emerges when there is unchecked activation of the innate immune and/or coagulation responses. Indeed, simultaneous excess coagulation and innate immune responses are evident in numerous diseases, including, for example, atherosclerosis, stroke, coronary heart disease and diabetes, as well as organ ischemia-reperfusion, the metabolic syndrome, and other vasculopathic disorders, such as age-related macular degeneration, and hemolytic-uremic syndrome.
With the discovery that common molecular mechanisms regulate coagulation and inflammation, the last decades have seen major progress in identifying the cellular and molecular links. However, there remain major gaps in our knowledge and new discoveries are urgently needed for the development of novel strategies to prevent and/or treat cardiovascular disease and stroke. In our lab, we characterize the interplay between coagulation and complement, seeking relevant applications to our discoveries, using pre-clinical and clinical modeling approaches.
- The perplexing story of the “tumor endothelial marker”, endosialin (CD248)
Endosialin (CD248) was originally identified as a tumor endothelial marker, but is now recognized to be expressed on the surface of activated stromal cells. This multi-domain glycoprotein is upregulated under pathologic conditions where it promotes inflammation and cell proliferation. Mice that lack CD248 are less sensitive to pro-inflammatory and oncogenic stimuli. Ongoing studies are designed to identify molecular mechanisms by which CD248 functions, the protein partners with which CD248 interacts, and the wider impact of changes in expression of CD248. The findings may provide novel avenues for therapeutic targeting.
Since inflammation and cancer are often associated with excess blood clotting, we aim to determine the mechanisms in the blood and on the blood vessel wall. This will allow the design of better therapies and preventative strategies to prevent thrombosis.
- Bergmeier W, Antoniak S, Conway EM, Denis CV, George LA, Isermann B, Key NS, Krishnaswamy S, Lam WA, Lillicrap D, Liu J, Looney MR, Lopez JA, Maas C, Peyvandi F, Ruf W, Sood AK, Versteeg HH, Wolberg AS, Wong PC, Wood JP, Weiler H. Advances in clinical and basic science of coagulation: Illustrated abstracts of the 9th Chapel Hill Symposium on Hemostasis. 2018 12;2(3):407-428. Res Pract Haemost.
- Loghmani H, Conway EM. Exploring traditional versusnon-traditional roles for thrombomodulin. 2018 132(2):148-158, Blood.
- Foley JH, Conway EM. Basic weapons to degrade C3a and C5a. 2018 16(5):987-990. Thromb. Haemost.
- Conway EM. Complement-coagulation connections. 2018, 29(3):243-251. Blood Coagulation Fibrinolysis.
- Pang SS, Wijeyewickrema LC, Hor L, Tan S, Lameignere E, Conway EM, Blom AM, Mohlin FC, Liu X, Payne RJ, Whisstock JC, Pike RN. The structural basis for complement inhibition by Gigastasin, a protease inhibitor from the giant Amazon Leech. 2017. 199(11):3883-3891 Immunology.
- Rand JH, Wu X-X, Wolgast LR, Lei V, Conway EM. A novel 2-stage approach that detects complement activation in patients with antiphospholipid antibody syndrome. 2017. 156:119-125 Thromb Res.
- Yang C-X, Singh A, Kim YW, Conway EM, Carlsten C, Tebbutt SJ. Diagnosis of western red cedar asthma using a blood-based gene expression biomarker panel. American Journal of Resp and Critical Care Med May 2, 2017 EPub PMID:28463537.
- Kalathottukaren M, Abraham L, Kapopara PR, Lai BFL, Shenoi RA, Rosell FI, Conway EM, Pryzdial ELF, Morrissey JH, Haynes CA, Kizhakkedathu JN. Alteration of clotting and clot morphology by protamine are avoided using the heparin and polyphosphate inhibitor, UHRA. Blood Mar 2017. 129(10):1368-1379.
- Cines DB, Yarovoi SV, Zaitsev S, Lebedeva T, Rauova L, Poncz M, Arepally GM, Rux AH, Cuker A, Guo C, Ocariza LM, Travers RJ, Smith SA, Kim H, Morrissey JH, Conway EM. Polyphosphate-platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia. Dec 2016. 29:128(3);1766-76. Blood Advances.
- Conway EM. Sweeteners for Factor H. Blood 127(22):2656-8.
11. Wijeyewickrema LC, Lameignere¬¬E, Hor L, Duncan RC, Shiba T, Travers RJ, Kapopaara PY, Lei V, Smith SA, Kim H, Morrissey JH, Pike RN, Conway EM. Polyphosphate is a novel cofactor for regulation of complement by the serpin C1-inhibitor. Blood 2016 128(13):1766-76.
- Foley JH, Conway EM. Crosstalk pathways between coagulation and inflammation. Circulation Research 2016 April 29:118(9):1392-408.
- Conway EM. A nuclear attack on thrombosis and inflammation. Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) Feb 36(2):221-3.
- Foley JH, Aleman MM, Walton, BL, O’Byrne AM, Lei V, Foley KA, Degen JL, Wolberg AS, Conway EM. Complement activation in arterial and venous thrombosis is mediated by plasmin. Lancet E-Biomedicine 2016 Feb 6;5:175-82.
- Foley JH, Conway EM. Gas6 gains entry into the coagulation cascade. Blood 2012 In Press.
- Foubert K, Breynaert A, Theunis M, Van Den Bossche R, De Meyer GR, Van Daele A, Faizal A, Goossens A, Geelen D, Conway EM, Vlietinck A, Pieters L, Apers S. Evaluation of the anti-angiogenic activity of saponins from Maesa lanceolata by different assays.Nature Prod Communications 2012 7(9):1149-54.
- Wang H, Vinnikov I, He T, Zhou Q, Shahzad K, Ranjan S, Wolter J, Kashif M, Oh J, Kirschfink M, Bierhaus A, Nawroth P, Conway EM, Madhusudhan T, Isermann B. The lectin-like domain of thrombomodulin ameliorates complement dependent diabetic nephropathy. Thromb Haemost 2012.108(6): EPub. PMID 23014597
- Iscru E,a Ahmed T, Coremans V, Bozzi Y, Caleo M, Conway EM, D’Hooge R, Balschun D. Loss of survivin in neural precursor cells results in impaired long-term potentiation in the dentate gyrus and CA1 region. Neuroscience 2012 In press.
- Zoja C, Locatelli M, Pagani C, Corna D, Isermann B, Remuzzi G, Conway EM, Noris M. Lack of the lectin-like domain of thrombomodulin worsens shiga toxin-associated HUS in mice. J. Immunology 2012. 189(7):3661-8.
- Schouten M, de Boer JD, van t Veer C, Roelofs JJTH, Meijers JCM, Levi MM, Conway EM, van der Poll T. The lectin-like domain of thrombomodulin hampers host defense in pneumoccoccal pneumonia. Eur Resp J 2012. Aug 30. Epub PMID 22936703
- Krisinger M, Goebeler V, Lu Z, Meixner SC, Myles T, Pryzdial ELG, Conway EM. Revising the terminal complement pathway: Thrombin generates previously unidentified C5 products which augment lytic activity. Blood 2012. 120(8):1717-25.
- Conway EM. Thrombomodulin and its role in inflammation. Seminars Immunopath. 2012. 34(1):107-125.
- Valdez Y, Maia M, Conway EM. CD248: Reviewing its role in health and disease. Curr Drug Targets 2012. Mar;13(3):432-439
- Conway EM. The Type XIV family of C-type lectin-like domain (CTLD) containing proteins. Curr Drug Targets 2012. Mar;13(3):409-410
- Martinez-Gutierrez F, Thi E, Silverman M, Camargo C, Svensson S, Vanden Hoek A, Reiner N, Gaynor E, Pryzdial ELG, Conway EM, Orrantia E, Ruiz F, Av-Gay Y, Bach H. Antibacterial activity, inflammatory response, coagulation and cytotoxicity effects of silver nanoparticles. Nanomedicine: Nanotechnology, Biology, and Medicine Jun 27, 2012 8(3):328-336.
- Conway EM. The clock is ticking as the clot is thickening. Arterioscler Thromb Vasc Biology. 2011. 31(11):2361-3
- Horowitz NA, Blevins EA, Miller WM, Perry AR, Talmage KE, Mullins ES, Flick MJ, Queiroz KCS, Shi K, Spek CA, Conway EM, Monia BP, Weiler H, Degen JL, Palumbo JS. Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain. Blood 2011. 118(10):2889-95.
- Maia M, DeVriese A, Janssens T, Moons M, Lories RJ, Tavernier J, Conway EM. CD248 facilitates tumor growth via its cytoplasmic domain. BMC Cancer 2011, 11:162.
- Takagi T, Taguchi O, D’Alessandro-Gabazza C, Toda M, Kobayashi T, Ruiz DB, Bernabe PG, Aoki S, Chiba F, Yano Y, Conway EM, Munesue S, Yamamoto Y, Yamamoto H, Suzuki K, Takei Y, Morser J, Gabazza EC. Inhibition of allergic bronchial asthma by thrombomodulin is mediated by dendritic cells. Am J Resp Critical Care Med 2011. 183(1):31-42.
- Maia M, DeVriese A, Janssens T, Moons M, Van Landuyt K, Tavernier J, Lories RJ, Conway EM. CD248 and its cytoplasmic domain: a therapeutic target for arthritis. Arthritis & Rheumatism 2010. 62(12):3595-606.
- Coremans V, Ahmed T, Balschun D, D’Hooge R, DeVriese A, Cremer J, Antonucci F, Moons M, Baekelandt V, Reumers V, Cremer H, Eisch A, Lagace D, Janssens T, Bozzi Y, Caleo M, Conway EM. Impaired neurogenesis, learning and memory and low seizure threshold associated with loss of neural precursor cell survivin. BMC Neuroscience Jan 5;11(1):2, 2010.
- Conway EM. Super factor B”-gets atypical HUS. Blood 2009. 114(13):2572-4
- Delvaeye M, Conway EM. Coagulation and innate Immune responses: Can they be viewed separately? Blood 2009. 114(2):2367-74.
- Delvaeye M, De Vriese A, Esmon CT, Esmon N, Ferrell G, Claes B, Lambrechts D, Remuzzi G, Noris M, Conway EM. Mutations in thrombomodulin in hemolytic-uremic syndrome. New England Journal of Medicine (IF 51) 361:345-357, 2009.
- Delvaeye M, De Vriese A, , Zwerts F, Betz I, Moons M, Autiero M, Conway EM. Role of the 2 zebrafish survivin genes in vasculo-angiogenesis, neurogenesis, cardiogenesis and hematopoiesis. BMC Developmental Biology 2009 Mar 26;9:25
- Geudens N, Van de Wouwer M, Banaudenaerde BM, Vos R, Van De Wauwer C, Verleden GM, Verbeken E, Lerut T, Van Raemdonck DEM, Conway EM. The lectin-like domain of thrombomodulin protects against ischemia-reperfusion lung injury. European Respiratory Journal, 2008, 32(4):862-70.
- 2016-2023 Tier 1 Canada Research Chair in Endothelial Cell Biology – $1,400,000
- 2017-2022 Natural Sciences Engineering Research Council of Canada – Discovering novel biochemical interactions between the complement and coagulation system – $250,000
- 2017-2022 Canadian Institutes for Health Research (operating) – Next generation antithrombotics: Safer inhibitors for thrombosis that targets procoagulant polyanions (coPIs Kizhakkedathu, Haynes) – $918,000
- 2018-2021 Heart and Stroke Foundation of Canada (operating) – Modulation of vascular function and thrombus formation by CD248 – $243,000
- 2018-2021 Collaborative Health Research Project (CIHR-NSERC partnered) – Platform technology for blook diagnostics integrating microneedle blood sampling and quantum-dot based multiplexed assays (coPIs Boris Stoeber, Walter Algar, Kizhakkedathu, Radoslav Staykov) – $256,025
- 2019-2024 Canadian Institutes for Health Research (operating) – Characterization of a novel cofactor for tissue factor (TF) that enhances its pro-thrombotic and pro-inflammatory activities – $826,200