Reference number : GC-2017-Q1-02569, amendment number : , agreement type : G, recipient legal name : Damjanovski, Sashko (The University of Western Ontario), recipient country : CA, recipient province : nan, recipient city : Ontario, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : Multicellular organisms are composed of trillions of cells held together by secreted extracellular matrix (ECM) proteins. Cells movement thus requires an orchestrated effort that involves cell communication, re-arrangements, and possibly the degradation of the ECM. Cell invasion is a type of cell migration through tissues that requires the degradation of the ECM. Cell migration is often activated by surface receptor triggered signalling cascades and changes in cell shape. Cell invasion, which is rare in adults, but crucial during embryogenesis and plays critical roles in adult wound healing, pregnancy, and in many diseases, is enabled by ECM degradation brought about by a family of 24 secreted enzymes called matrix metalloproteinases (MMPs). MMPs are often expressed in both migrating and invading cells. But the movement of cells through tissues is not simply dependent on ECM degradation, as inhibiting MMP enzymatic activity is not always associated with impaired migration nor invasion. Our objectives are to identify the roles played by a key membrane type MMP, MT1-MMP in orchestrating the movement of cells. While lack of MMP presence during embryogenesis does results in inappropriate ECM remodelling and associated vascular and skeletal defects, only the lack of MT1-MMP is embryonic lethal. While most MMPs are released from the cell surface, membrane bound MT1-MMP can also transduce signals into the cell. This, and our more recent work in frog and with 2D and 3D cell cultures has demonstrated a fundamental role for MT1-MMP, one which we believe is key to governing cell movement. MT1-MMP can; 1) cleave the ECM, 2) regulate the activity of other MMPs, 3) binds in a receptor-like fashion to a variety of secreted molecule, 4) activate intracellular signalling cascades that regulates gene expression and cell morphology. 
Taken together we will investigate roles of the enzymatic and non-enzymatic functions of MT1-MMP in regulating cell movement &ndash; migration and invasion. We have evidence that while inhibiting the enzymatic activity of MT1-MMP does indeed reduce ECM degradation and often invasion, it does not alter migration. Changes to MT1-MMP levels, activity, and alterations to its signalling domains all result in consistent changes in gene expression and cell morphology that is not related to its enzymatic function. It has distinct enzymatic and non-enzymatic roles. We will use cells that are engineered to contain various levels and functional domains of active MT1-MMP to investigate the ability of these cells to migrate and/or invade in response to both ligand binding to MT1-MMP, as well as the addition of known cell migratory cues. Understanding MT1-MMP&rsquo;s non-enzymatic role in facilitating cell signalling and changes in cell morphology, along with coordinating its enzymatic role in degrading the ECM, is crucial to our understanding of cell invasion, a process critical to so many embryonic events., program purpose french : Multicellular organisms are composed of trillions of cells held together by secreted extracellular matrix (ECM) proteins. Cells movement thus requires an orchestrated effort that involves cell communication, re-arrangements, and possibly the degradation of the ECM. Cell invasion is a type of cell migration through tissues that requires the degradation of the ECM. Cell migration is often activated by surface receptor triggered signalling cascades and changes in cell shape. Cell invasion, which is rare in adults, but crucial during embryogenesis and plays critical roles in adult wound healing, pregnancy, and in many diseases, is enabled by ECM degradation brought about by a family of 24 secreted enzymes called matrix metalloproteinases (MMPs). MMPs are often expressed in both migrating and invading cells. But the movement of cells through tissues is not simply dependent on ECM degradation, as inhibiting MMP enzymatic activity is not always associated with impaired migration nor invasion. Our objectives are to identify the roles played by a key membrane type MMP, MT1-MMP in orchestrating the movement of cells. While lack of MMP presence during embryogenesis does results in inappropriate ECM remodelling and associated vascular and skeletal defects, only the lack of MT1-MMP is embryonic lethal. While most MMPs are released from the cell surface, membrane bound MT1-MMP can also transduce signals into the cell. This, and our more recent work in frog and with 2D and 3D cell cultures has demonstrated a fundamental role for MT1-MMP, one which we believe is key to governing cell movement. MT1-MMP can; 1) cleave the ECM, 2) regulate the activity of other MMPs, 3) binds in a receptor-like fashion to a variety of secreted molecule, 4) activate intracellular signalling cascades that regulates gene expression and cell morphology. 
Taken together we will investigate roles of the enzymatic and non-enzymatic functions of MT1-MMP in regulating cell movement &ndash; migration and invasion. We have evidence that while inhibiting the enzymatic activity of MT1-MMP does indeed reduce ECM degradation and often invasion, it does not alter migration. Changes to MT1-MMP levels, activity, and alterations to its signalling domains all result in consistent changes in gene expression and cell morphology that is not related to its enzymatic function. It has distinct enzymatic and non-enzymatic roles. We will use cells that are engineered to contain various levels and functional domains of active MT1-MMP to investigate the ability of these cells to migrate and/or invade in response to both ligand binding to MT1-MMP, as well as the addition of known cell migratory cues. Understanding MT1-MMP&rsquo;s non-enzymatic role in facilitating cell signalling and changes in cell morphology, along with coordinating its enzymatic role in degrading the ECM, is crucial to our understanding of cell invasion, a process critical to so many embryonic events., agreement title english : MT1-MMP regulation of matrix degradation and cell movement., agreement title french : MT1-MMP regulation of matrix degradation and cell movement., agreement number : RGPIN, agreement value : 26000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2018-2019), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2018-2019), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada