Reference number : GC-2017-Q1-02800, amendment number : , agreement type : G, recipient legal name : BIROT, Olivier (York University)|BIROT, Olivier (Université York), 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 : Capillaries are our smallest blood vessels. They are the site of exchanges between blood and cells. In skeletal muscles, capillaries play a crucial role in providing oxygen and nutrients to the active muscle cells. Angiogenesis is the very complex process of formation of new capillaries. Physical exercise is a well-known stimulus for skeletal muscle angiogenesis. One single bout of exercise stimulates the expression of signal molecules that regulate the process of muscle angiogenesis. In particular, these molecules act on endothelial cells, the cells forming the wall of the capillaries. In order to get more capillaries, these cells need to be activated so they can proliferate, migrate, and assembly together into new vessels. If the exercise stimulus is repeated daily over a few weeks, like during prolonged exercise training, new functional capillaries will be formed in skeletal muscle, and the muscle function, especially in response to exercise, will be improved. 
 
 Research in my laboratory aims to identify and to understand the cellular and molecular mechanisms that regulate angiogenesis in skeletal muscle. 
 
With my previous NSERC Discovery Grant, we have demonstrated that a molecule named Murine Minute Double-2 (Mdm2) was a key regulator of muscle angiogenesis during exercise. We have observed that exercise strongly activates Mdm2 in skeletal muscle. At the level of the muscle tissue, we have shown that activated Mdm2 was stimulating the expression of several molecules known to activate endothelial cells during exercise. Using endothelial cell culture in vitro, we have then discovered that activated Mdm2 was strongly stimulating the migration of these cells, which is a crucial step in the assembly of endothelial cells to form new capillaries. This research was conducted at the muscle tissue level and in cultured endothelial cells . In the the research program proposed here, our goal will be to focus on the role that Mdm2 could play on angiogenesis specifically at the level of contractile muscle cells . We think that exercise could stimulate Mdm2 activation in muscle cells, leading to the production and release of signal molecules that will in turn act on the neighbouring endothelial cells to stimulate the formation of new capillaries. 
 
This will be achieved through three independent research aims. 
 
 Aim #1. To characterize in vivo in muscle tissue and in vitro in cultured muscle cells the effect of exercise on Mdm2 and its activated form. 
 
Aim #2. To investigate in vitro in cultured muscle cells what is the mechanism of action of Mdm2 and its activated form. 
 
Aim #3. To investigate in vivo in muscle tissue, specifically at the level of muscle cells taken into the whole muscle context, what is the mechanism of action of Mdm2 and its activated form. 
 
Our research program will provide new knowledge in the field of muscle physiology and Mdm2 biology. It will also contribute to the formation of Highly Qualified Personal in Canada., program purpose french : Capillaries are our smallest blood vessels. They are the site of exchanges between blood and cells. In skeletal muscles, capillaries play a crucial role in providing oxygen and nutrients to the active muscle cells. Angiogenesis is the very complex process of formation of new capillaries. Physical exercise is a well-known stimulus for skeletal muscle angiogenesis. One single bout of exercise stimulates the expression of signal molecules that regulate the process of muscle angiogenesis. In particular, these molecules act on endothelial cells, the cells forming the wall of the capillaries. In order to get more capillaries, these cells need to be activated so they can proliferate, migrate, and assembly together into new vessels. If the exercise stimulus is repeated daily over a few weeks, like during prolonged exercise training, new functional capillaries will be formed in skeletal muscle, and the muscle function, especially in response to exercise, will be improved. 
 
 Research in my laboratory aims to identify and to understand the cellular and molecular mechanisms that regulate angiogenesis in skeletal muscle. 
 
With my previous NSERC Discovery Grant, we have demonstrated that a molecule named Murine Minute Double-2 (Mdm2) was a key regulator of muscle angiogenesis during exercise. We have observed that exercise strongly activates Mdm2 in skeletal muscle. At the level of the muscle tissue, we have shown that activated Mdm2 was stimulating the expression of several molecules known to activate endothelial cells during exercise. Using endothelial cell culture in vitro, we have then discovered that activated Mdm2 was strongly stimulating the migration of these cells, which is a crucial step in the assembly of endothelial cells to form new capillaries. This research was conducted at the muscle tissue level and in cultured endothelial cells . In the the research program proposed here, our goal will be to focus on the role that Mdm2 could play on angiogenesis specifically at the level of contractile muscle cells . We think that exercise could stimulate Mdm2 activation in muscle cells, leading to the production and release of signal molecules that will in turn act on the neighbouring endothelial cells to stimulate the formation of new capillaries. 
 
This will be achieved through three independent research aims. 
 
 Aim #1. To characterize in vivo in muscle tissue and in vitro in cultured muscle cells the effect of exercise on Mdm2 and its activated form. 
 
Aim #2. To investigate in vitro in cultured muscle cells what is the mechanism of action of Mdm2 and its activated form. 
 
Aim #3. To investigate in vivo in muscle tissue, specifically at the level of muscle cells taken into the whole muscle context, what is the mechanism of action of Mdm2 and its activated form. 
 
Our research program will provide new knowledge in the field of muscle physiology and Mdm2 biology. It will also contribute to the formation of Highly Qualified Personal in Canada., agreement title english : Investigating the angiogenic role of Murine Double Minute-2 in contractile muscle cells, agreement title french : Investigating the angiogenic role of Murine Double Minute-2 in contractile muscle cells, agreement number : RGPIN, agreement value : 140000.0, 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