Reference number : GC-2017-Q1-03277, amendment number : , agreement type : G, recipient legal name : Robinson, Lisa (University of Toronto), 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 : In vertebrate animals, white blood cells play an important role in the immune system by protecting against bacterial, fungal, and viral infections. White blood cells patrol the body looking for signs of infection. This immune surveillance involves interactions between white cells and the cells lining blood vessels. White cells are recruited to areas of injury by various signals, especially molecules called chemokines. Among the family of chemokines, one member, CX 3 CL1, is anchored to the surface of cells lining blood vessels, and CX 3 CL1 both attracts white cells and physically attaches them to blood vessels.
 
 
CX 3 CL1 is released from the surface of blood vessel cells after being cut by ADAM17, an enzyme that acts as molecular scissors. However, the way in which ADAM17 makes contact with and cuts CX 3 CL1 is not well understood. Our preliminary work suggests that CX 3 CL1 is normally restricted within fenced corrals along the surface of blood vessel cells, and that it is segregated from ADAM17. Using state-of-the-art microscopy techniques, we will examine how CX 3 CL1 at the surface of the cell is confined. Specifically, we will determine whether CX 3 CL1 is tethered to the internal skeleton that maintains the shape of the cell, or whether molecules secreted outside the cell trap CX 3 CL1 within their mesh. We will also examine whether ADAM17 cuts CX 3 CL1 at the cell surface or in a separate compartment inside the cell, and how ADAM17 gains access to CX 3 CL1. Lastly, we will determine how release of CX 3 CL1 affects the barrier integrity of blood vessel cells, and their ability to recruit white blood cells. By understanding the molecular details, our studies will shed light on a fundamental process of immune cell patrolling conserved among vertebrate animals. Our work will further clarify the way in which the ADAM17 molecular scissors can selectively cut different types of molecules under different physical conditions., program purpose french : In vertebrate animals, white blood cells play an important role in the immune system by protecting against bacterial, fungal, and viral infections. White blood cells patrol the body looking for signs of infection. This immune surveillance involves interactions between white cells and the cells lining blood vessels. White cells are recruited to areas of injury by various signals, especially molecules called chemokines. Among the family of chemokines, one member, CX 3 CL1, is anchored to the surface of cells lining blood vessels, and CX 3 CL1 both attracts white cells and physically attaches them to blood vessels.
 
 
CX 3 CL1 is released from the surface of blood vessel cells after being cut by ADAM17, an enzyme that acts as molecular scissors. However, the way in which ADAM17 makes contact with and cuts CX 3 CL1 is not well understood. Our preliminary work suggests that CX 3 CL1 is normally restricted within fenced corrals along the surface of blood vessel cells, and that it is segregated from ADAM17. Using state-of-the-art microscopy techniques, we will examine how CX 3 CL1 at the surface of the cell is confined. Specifically, we will determine whether CX 3 CL1 is tethered to the internal skeleton that maintains the shape of the cell, or whether molecules secreted outside the cell trap CX 3 CL1 within their mesh. We will also examine whether ADAM17 cuts CX 3 CL1 at the cell surface or in a separate compartment inside the cell, and how ADAM17 gains access to CX 3 CL1. Lastly, we will determine how release of CX 3 CL1 affects the barrier integrity of blood vessel cells, and their ability to recruit white blood cells. By understanding the molecular details, our studies will shed light on a fundamental process of immune cell patrolling conserved among vertebrate animals. Our work will further clarify the way in which the ADAM17 molecular scissors can selectively cut different types of molecules under different physical conditions., agreement title english : Metalloprotease-Substrate Interactions in Endothelial Cells, agreement title french : Metalloprotease-Substrate Interactions in Endothelial Cells, agreement number : RGPIN, agreement value : 250000.0, 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 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), 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