Paris Margaritis, D.Phil

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Research Assistant Professor of Pediatrics
Department: Pediatrics

Contact information
Rm 5024 Colket Translational Research Building
The Children's Hospital of Philadelphia
3501 Civic Center Blvd.
Philadelphia, PA 19104
Office: 2674267262
Fax: 2155903660
Lab: 2674267262
Education:
BSc (Hons) (Genetics)
The University of Newcastle-upon-Tyne (UK), 1995.
DPhil (Molecular Biology and Gene Therapy)
The University of Oxford (UK), 2000.
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Description of Research Expertise

Our research pivots on a unique model that we have developed, whereby we can enhance the extrinsic pathway of coagulation by raising the circulating levels of activated FVII (FVIIa) in animal models. Such an approach has obvious ramifications as a potential treatment for coagulation disorders that are currently treated with recombinant FVIIa. Indeed, in a series of novel experiments in life models with hemophilia, we showed that expression of FVIIa via gene transfer results in dramatic phenotypic improvements or complete correction. In addition, we developed mouse and canine-specific reagents, assays and endpoints that allow us to monitor in vivo effects in hemostasis resulting from the action of FVIIa. A current line of investigation in our laboratory aims to better define the intricacies of viral transduction-based FVIIa gene expression and its hemostatic effects in animal models of hemophilia.

The general concept of coagulation proteases interacting with factors other than their natural ligands also applies to FVIIa. Its binding to cell-surface receptors other than tissue factor pose intriguing questions on previously unconsidered interactions affecting its function. As a result, part of ongoing work in our laboratory is a new line of investigation that focuses on the molecular interactions between FVIIa and its binding partners and how these relate to the hemostatic and other role(s) of FVIIa in vivo. To address these functions we have developed unique in vitro and in vivo methodologies to define, quantitate and even visualize FVIIa-participating reactions as they occur in real time. Exploiting this information may also form the basis for the rational design FVIIa-based therapeutics, either protein or gene-based, that can be used for the treatment of coagulation defects.

Selected Publications

Pavani Giulia, Zintner Shannon M., Ivanciu Lacramioara, Small Julianna C., Stafford Katherine A., Szeto Julia H. and Margaritis Paris : One amino acid in mouse factor VIIa defines its endothelial protein C receptor (EPCR) binding and modulates its EPCR-dependent hemostatic activity in vivo. Journal of Thrombosis and Haemostasis 15(3): 507-512, Mar 2017.

Marcos-Contreras Oscar A., Smith Shannon M., Bellinger Dwight A., Raymer Robin A., Merricks Elizabeth, Faella Armida, Pavani Giulia, Zhou Shangzhen, Nichols Timothy C., High Katherine A., Margaritis Paris: Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII. Blood 127(5): 565-71, Feb 2016.

Pavani Giulia, Ivanciu Lacramioara, Faella Armida, Marcos-Contreras Oscar A. and Margaritis Paris: The endothelial protein C receptor enhances hemostasis of FVIIa administration in hemophilic mice in vivo. Blood 124(7): 1157-65, Aug 2014.

Balestra Dario, Faella Armida, Margaritis Paris, Cavallari Nicola, Pagani Franscesco, Bernardi Franscesco, Arruda Valder R., Pinotti Mirko: An engineered U1 small nuclear RNA rescues splicing-defective coagulation F7 gene expression in mice. Journal of Thrombosis and Haemostasis 12(2): 177-85, Feb 2014.

Yazicioglu Mustafa N., Monaldini Luca, Chu Kirk, Khazi Fayaz R., Murphy Samuel L., Huang Heshu, Margaritis Paris, High Katherine A.: Cellular Localization and Characterization of Cytosolic Binding Partners for Gla-containing Proteins PRRG4 and PRRG2. Journal of Biological Chemistry 288(36): 25908-14, Sep 2013.

Scola Mallory R, Nichols Timothy C, Zhu Hongtu, Caughey Melissa C, Merricks Elizabeth P, Raymer Robin A, Margaritis Paris, High Katherine A, Gallippi Caterina M: ARFI ultrasound monitoring of hemorrhage and hemostasis in vivo in canine von Willebrand disease and hemophilia. Ultrasound in Medicine & Biology 37(12): 2126-32, Dec 2011.

Ivanciu Lacramioara, Toso Raffaella, Margaritis Paris, Pavani Giulia, Kim Haein, Schlachterman Alexander, Liu Jian-Hua, Clerin Valerie, Pittman Debra D, Rose-Miranda Rosalind, Shields Kathleen M, Erbe David V, Tobin James F, Arruda Valder R, Camire Rodney M: A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia. Nature Biotechnology 29(11): 1028-33, Nov 2011.

Zheng Xing-Wu, Kudaravalli Rama, Russell Theresa T, DiMichele Donna M, Gibb Constance, Russell J Eric, Margaritis Paris, Pollak Eleanor S: Mutation in the factor VII hepatocyte nuclear factor 4α-binding site contributes to factor VII deficiency. Blood Coagulation & Fibrinolysis 22(7): 624-7, Oct 2011.

Margaritis Paris, Roy Elise, Faella Armida, Downey Harre D, Ivanciu Lacramioara, Pavani Giulia, Zhou Shangzhen, Bunte Ralph M, High Katherine A: Catalytic domain modification and viral gene delivery of activated factor VII confers hemostasis at reduced expression levels and vector doses in vivo. Blood 117(15): 3974-82, Apr 2011.

Margaritis Paris, Roy Elise, Aljamali Majed N, Downey Harre D, Giger Urs, Zhou Shangzhen, Merricks Elizabeth, Dillow Aaron, Ezban Mirella, Nichols Timothy C, High Katherine A: Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood 113(16): 3682-9, Apr 2009.

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Last updated: 11/12/2017
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