Reference number : GC-2017-Q1-02597, amendment number : , agreement type : G, recipient legal name : Jacobs, J Roger (McMaster University), 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 : The aim of this proposal is to reveal the mechanisms of cell-to-extracellular matrix (ECM) interaction that regulate development and reshaping of organs like the heart. The ECM is a network of glycoproteins and proteoglycans that are the substrate that bears cell and tissue tension, which also protects tissues and provides a source of molecules that instruct the behavior of cells. Here I propose experiments to test the hypothesis that adhesion signals communicate information that modifies the composition, spatial organisation and physical properties of local ECM. My program employs the fruitfly heart as a genetic model with simple morphology, and focus on the activity of extracellular digestive enzymes (proteases) on cardiac ECM throughout development and aging. Our published works demonstrate that ongoing changes in heart muscle adhesion signaling affect heart form and function. We established that the size and location of the inner vessel wall is regulated by the activity of the two Matrix MetalloProteases (MMPs). This provides the backdrop for our analysis of how changes in ECM composition and organisation remodel tissue form and function. This work supports a deeper understanding of how extracellular mechanisms generate diversity of morphology and respond to external factors during growth and aging. 
 Three AIMs are addressed: 
 1. Reveal how ECM proteases enable heart tube formation . Protein distribution suggests that specific signals inside each cell (intracellular targeting, lipid signalling and GTPase messengers) are differentially restricted to Cadherin expressing or Integrin expressing apical membrane. We will manipulate expression or function of these signals in embryonic heart cells to determine whether the location of Integrins, MMPs or local ECM acts upstream of these signals. 
 2. Determine how each cell type contributes to ECM remodeling. Our preliminary findings revealed a close association between the ECM of the larval heart and clusters of blood cells (haemocytes). Haemocytes also accumulate at malformed regions of the heart. We will use genetic tools to alter haemocyte homing signals or function to determine whether these cells paly a role in ECM remodeling. 
 3. Determine whether heart physiology can inform ECM remodeling. Drosophila provides a unique model where receptors that signal cardiac load (such as Integrin), or the expression of genes that respond to cardiac load can be temporally altered. We will express transgenes in the heart that make the muscle less efficient, and characterise the changes in ECM structure and composition. Further, we will determine whether haemocytes or muscle cells regulate these changes, and explore what signals may be employed to trigger the response., program purpose french : The aim of this proposal is to reveal the mechanisms of cell-to-extracellular matrix (ECM) interaction that regulate development and reshaping of organs like the heart. The ECM is a network of glycoproteins and proteoglycans that are the substrate that bears cell and tissue tension, which also protects tissues and provides a source of molecules that instruct the behavior of cells. Here I propose experiments to test the hypothesis that adhesion signals communicate information that modifies the composition, spatial organisation and physical properties of local ECM. My program employs the fruitfly heart as a genetic model with simple morphology, and focus on the activity of extracellular digestive enzymes (proteases) on cardiac ECM throughout development and aging. Our published works demonstrate that ongoing changes in heart muscle adhesion signaling affect heart form and function. We established that the size and location of the inner vessel wall is regulated by the activity of the two Matrix MetalloProteases (MMPs). This provides the backdrop for our analysis of how changes in ECM composition and organisation remodel tissue form and function. This work supports a deeper understanding of how extracellular mechanisms generate diversity of morphology and respond to external factors during growth and aging. 
 Three AIMs are addressed: 
 1. Reveal how ECM proteases enable heart tube formation . Protein distribution suggests that specific signals inside each cell (intracellular targeting, lipid signalling and GTPase messengers) are differentially restricted to Cadherin expressing or Integrin expressing apical membrane. We will manipulate expression or function of these signals in embryonic heart cells to determine whether the location of Integrins, MMPs or local ECM acts upstream of these signals. 
 2. Determine how each cell type contributes to ECM remodeling. Our preliminary findings revealed a close association between the ECM of the larval heart and clusters of blood cells (haemocytes). Haemocytes also accumulate at malformed regions of the heart. We will use genetic tools to alter haemocyte homing signals or function to determine whether these cells paly a role in ECM remodeling. 
 3. Determine whether heart physiology can inform ECM remodeling. Drosophila provides a unique model where receptors that signal cardiac load (such as Integrin), or the expression of genes that respond to cardiac load can be temporally altered. We will express transgenes in the heart that make the muscle less efficient, and characterise the changes in ECM structure and composition. Further, we will determine whether haemocytes or muscle cells regulate these changes, and explore what signals may be employed to trigger the response., agreement title english : The role of spatial and temporal regulation of Extracellular Matrix composition by Matrix Metalloproteases during development, growth and aging of the Drosophila heart, agreement title french : The role of spatial and temporal regulation of Extracellular Matrix composition by Matrix Metalloproteases during development, growth and aging of the Drosophila heart, agreement number : RGPIN, agreement value : 200000.0, 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