Gamma-glutamyl carboxylase (GGCX) is an enzyme essential for the post-translational modification of glutamic acid residues found within the gamma-carboxyglutamic acid (GLA) domain of vitamin K-dependent blood coagulation factors as well as other proteins principally involved in bone development such as Osteocalcin and Matrix Gla Protein. We propose that Marrow Stromal Cells (MSC) may serve as a useful Factor IX (FIX) delivery vehicle in vivo. As part of the validation of this cellular delivery platform for gene therapy, we determined whether MSCs endogenously express the GGCX gene. We demonstrated that GGCX was present in MSCs and that it was upregulated as MSCs differentiate into osteoblasts. These results will be of use in the rational development of Marrow Stromal Cells as a delivery vehicle of synthetic gamma-carboxylated therapeutic proteins, including FIX for therapy of Hemophilia B. Furthermore, we wanted to improve upon factor IX gamma-glutamyl carboxylation by generating a fusion FIX protein with enhance carboxylation capabilities. We interchanged the propeptide responsible of the efficiency of this post-translational process of factor IX by the one of the most efficiently gamma-carboxylated proteins, prothrombin.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.80310 |
| Date | January 2003 |
| Creators | Landry, Sebastien |
| Contributors | Galipeau, Jacques (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002031992, proquestno: AAIMQ98679, Theses scanned by UMI/ProQuest. |
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