Reference number : GC-2017-Q1-03170, amendment number : , agreement type : G, recipient legal name : Jia, Zhengping (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 : Title: Regulation of mammalian brain development by p21-activated kinase signaling pathways 
 
This application is a renewal of my current NSERC discovery grant (RGPIN341498, 2012-2017). 
 
The long-term goal of my research program is to understand the fundamental mechanisms that govern brain development and function. To this end, we have identified a number of molecules that are important for neuronal proliferation, survival, migration, morphogenesis and maturation, a series of highly regulated processes critical for normal brain growth, neural circuit formation and function. With particular relevance to this application and with the funding of my current NSERC discovery grant (2012-17), we have demonstrated that knockout (KO) mice lacking the p21-activated kinases (PAKs), a family of protein kinases known to be important for cytoskeletal reorganization, are altered in brain size, cortical volume, neuronal progenitor cell division and migration. Significantly, these KO mice are defective in the activity of LIM-kinase 1 (LIMK1) and the actin-binding protein cofilin, both of which are key targets of PAKs important for actin regulation. Furthermore, we discovered that PAKs can exert effects on the endocannabinoid (eCB) system, an emerging player in various aspects of embryonic brain development. These results lead to a hypothesis that PAKs regulate cortical development via coordinating actin reorganization and eCB signaling. To address this hypothesis, we will use multiple techniques, including mouse genetics, immunohistochemistry, imaging, biochemical assays and electrophysiological recordings to achieve three specific aims: 
 
 Aim 1 . To determine the relative contribution of PAK1 and 3 in neuronal proliferation and migration by labeling and tracking neural progenitor cells in various PAK KO mice. 
 
 Aim 2. To determine the role of PAK1 and 3 in early postnatal neuronal morphogenesis and synaptic maturation by analyzing neuronal and synaptic morphology. 
 
 Aim 3. To elucidate the molecular mechanisms underlying PAK1/3 actions by investigating the role of LIMK1/cofilin and eCB signaling. 
 
The results from this application will reveal the in vivo function and underlying mechanisms by which PAK signaling regulates cortical and neuronal development. This will in turn contribute to my long-term goal to understand the fundamental process governing brain development and function. Since both cortical malformations and PAKs are closely associated with many neurological and mental disorders, this proposal will also provide new insight into the pathogenesis and treatment of these diseases., program purpose french : Title: Regulation of mammalian brain development by p21-activated kinase signaling pathways 
 
This application is a renewal of my current NSERC discovery grant (RGPIN341498, 2012-2017). 
 
The long-term goal of my research program is to understand the fundamental mechanisms that govern brain development and function. To this end, we have identified a number of molecules that are important for neuronal proliferation, survival, migration, morphogenesis and maturation, a series of highly regulated processes critical for normal brain growth, neural circuit formation and function. With particular relevance to this application and with the funding of my current NSERC discovery grant (2012-17), we have demonstrated that knockout (KO) mice lacking the p21-activated kinases (PAKs), a family of protein kinases known to be important for cytoskeletal reorganization, are altered in brain size, cortical volume, neuronal progenitor cell division and migration. Significantly, these KO mice are defective in the activity of LIM-kinase 1 (LIMK1) and the actin-binding protein cofilin, both of which are key targets of PAKs important for actin regulation. Furthermore, we discovered that PAKs can exert effects on the endocannabinoid (eCB) system, an emerging player in various aspects of embryonic brain development. These results lead to a hypothesis that PAKs regulate cortical development via coordinating actin reorganization and eCB signaling. To address this hypothesis, we will use multiple techniques, including mouse genetics, immunohistochemistry, imaging, biochemical assays and electrophysiological recordings to achieve three specific aims: 
 
 Aim 1 . To determine the relative contribution of PAK1 and 3 in neuronal proliferation and migration by labeling and tracking neural progenitor cells in various PAK KO mice. 
 
 Aim 2. To determine the role of PAK1 and 3 in early postnatal neuronal morphogenesis and synaptic maturation by analyzing neuronal and synaptic morphology. 
 
 Aim 3. To elucidate the molecular mechanisms underlying PAK1/3 actions by investigating the role of LIMK1/cofilin and eCB signaling. 
 
The results from this application will reveal the in vivo function and underlying mechanisms by which PAK signaling regulates cortical and neuronal development. This will in turn contribute to my long-term goal to understand the fundamental process governing brain development and function. Since both cortical malformations and PAKs are closely associated with many neurological and mental disorders, this proposal will also provide new insight into the pathogenesis and treatment of these diseases., agreement title english : Regulation of mammalian brain development by p21-activated kinase signaling pathways, agreement title french : Regulation of mammalian brain development by p21-activated kinase signaling pathways, 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