CVI Program Unit(s):
Thrombosis / Hemostasis
CVI Research Description:
My laboratory is interested in understanding the components of the blood coagulation system, how they interface with activated cells, and how disturbances in their function lead to bleeding and thrombosis. We are also interested in developing therapeutic approaches (protein and gene-based) to mitigate these events which are major causes of morbidity and mortality worldwide. We are interested in questions related to the enzymology, biochemistry, and molecular genetics of enzyme complexes involved in blood coagulation. Numerous systems are employed to answer these questions including kinetic, biophysical, and structural approaches in addition to using in vivo models to make meaningful contributions to the field. The current areas of investigation in the laboratory include:
1. Molecular basis of procofactor activation: We are interested in understanding how FV and FVIII are preserved as inactive procofactors and defining their mechanism of activation. Our work has uncovered surprising and unexpected observations that have fundamentally shifted current thinking about FV activation and its regulation by TFPI.
2. Structural correlates of protease function-basic and translational research: We seek to better understand how processing of inactive serine protease zymogens such as FX and FIX, to their active forms contributes to the expression of binding sites critical to their function. Knowledge from these biochemical studies has been applied to translational studies, some in collaboration with companies, to develop novel protein therapeutics to treat bleeding in hemophilia, trauma, or other conditions.
3. Imaging coagulation reactions in vivo. We have taken advantage of fluorescence approaches developed for physical studies of coagulation enzyme function to develop enabling technologies that permit quantitative measurements of enzyme complex assembly and function in vivo.
4. Employ gene therapy strategies for hemophilia A/B by employing novel modifications to the protein cofactor, factor VIII or zymogen FIX. Using different bioengineering strategies we are interested in modifying FVIII or FIX with unique properties that could be useful in a gene-based approach.
Selected Publications
Ivanciu L, Arruda VR, Camire RM.: Factor IXa variants resistant to plasma inhibitors enhance clot formation in vivo. Blood Feb 2023.
Ayombil F, Petrillo T, Kim H, Camire RM.: Regulation of factor V by the anticoagulant protease activated protein C: Influence of the B-domain and TFPIα J Biol Chem 298(11): 102558-102568, Sep 2022.
Maag A, van Rein N, Schuijt TJ, Kopatz WF, Kruijswijk D, Thomassen S, Hackeng TM, Camire RM, van der Poll T, Meijers JCM, Bos MHA, van 't Veer C.: Major bleeding during oral anticoagulant therapy associated with factor V activation by factor Xa. J Thromb Haemost 20(2): 328-338, 2022.
Milstone LM, Jackson C, Becker RC, Camire R, Knabb R, Mann K, Ruf W, Wexler RR, Wood J.: Discussion of talks from the symposium: Factor X: From thrombokinase to oral anti-coagulants and beyond. J Thromb Thrombolysis 52(2): 408-413, Oct 2021.
Borst S, Nations CC, Klein JG, Pavani G, Maguire JA, Camire RM, Drazer MW, Godley LA, French DL, Poncz M, Gadue P.: Study of inherited thrombocytopenia resulting from mutations in ETV6 or RUNX1 using a human pluripotent stem cell model. Stem Cell Reports 16: 1458-1467, Jun 2021.
Petrillo, T., Ayombil, F., van't Veer, C., and Camire, R.M: Regulation of factor V and factor V-short by TFPIα: Relationship between B-domain proteolysis and binding. J. Biol. Chem. 296: 100234, Jan 2021 Notes: Editors' Picks; DOI:https://doi.org/10.1074/jbc.RA120.016341.
Samelson-Jones, B.J., Finn, J.D., Chau, J., Chen, Z. Raffini, L.J., Merricks, E.P., Camire, R.M., Nichols, T.C., and Arruda, V.R: Evolutionary insights into coagulation factor IX Padua and other high-specific-activity variants. Blood Advances 5(5): 1324-1332, 2021.
Zimowski KL, Petrillo T, Ho MD, Wechsler J, Shields JE, Denning G, Jhita N, Rivera AA, Escobar MA, Kempton CL, Camire RM, Doering CB.: F5-Atlanta: A novel mutation in F5 associated with enhanced East Texas splicing and FV-short production. J. Thromb. Haemost. 19(7): 1653-1665, 2021 Notes: DOI: 10.1111/jth.15314.
Wilhelm, A.R., Parsons, N.A., Samelson-Jones, B.J., Davidson, R.J., Esmon, C.T., Camire, R.M., and George, L.A: Activated protein C has a regulatory role in factor VIII function. Blood 137(18): 2532-2543, 2021 Notes: DOI: 10.1182/blood.2020007562
Ayombil, A. and Camire, R.M: Insights into vitamin K-dependent carboxylation: home field advantage. Haematologica 105(8): 1996-1998, 2020.
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Last updated: 03/22/2023
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