Reference number : GC-2017-Q1-02277, amendment number : , agreement type : G, recipient legal name : Gold, Michael (The University of British Columbia), recipient country : CA, recipient province : nan, recipient city : British Columbia|Colombie-Britannique, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : Cells, organs, and organisms must respond to changes in their environment. The immune system is an excellent model of how sensing and alerting functions are integrated. Innate immune cells such as macrophages have receptors on their surface that capture pathogens, recognize microbial components as danger signals, and initiate immediate protective responses. If the infection is not cleared, T- and B-lymphocytes of the adaptive immune system are activated to generate more potent and specific responses (e.g. antibodies). Key intermediates are innate-like lymphocytes such as marginal zone B cells (MZBs), which detect pathogens, alert adaptive immune cells, and provide protection until the adaptive immune system is activated. 
MZBs reside at sites where the blood or lymph enters lymphoid organs. They express B cell receptors (BCR) that bind specific parts of foreign molecules (antigens [Ags]), as well as Toll-like receptors (TLRs) that bind microbial danger signals. The activation of MZBs by Ags and microbial components causes them to secrete antibodies that recognize broad classes of microbes. However, MZBs also play a key role in alerting other cells of the immune system. They capture Ags via the BCR and other receptors (CD21, CD36) on their surface. This allows them to promote the activation of T cells as well as circulating B cells that make highly specific antibodies. Although MZBs are important early responders, their cell biology has not been studied because they are few in number and no MZB cell lines exist. My lab has developed expertise in studying MZBs using single cell microscopy and our goal is to elucidate the mechanisms that allow them to be effective sensing/alerting cells. 
We found that MZBs rapidly extend a network of long, thin membrane protrusions called filopodia. This resembles the dendritic network of sensory neurons. We hypothesize that the MZB filopodial network (FilNet) is a sensory apparatus that is specialized for detecting microbes and acquiring Ags. The factors that regulate MZB FilNet formation are not known and its role as a sensory and Ag-acquisition apparatus has not been explored. 
The objectives of this proposal are to test the following hypotheses: 
(1) Sensory receptors (BCR, TLRs) and Ag acquisition receptors (BCRs, CD21, CD36) are present on MZB filopodia 
(2) Adhesion molecules, TLRs, hormones that MZBs are normally exposed to, and inflammatory mediators regulate the formation of MZB FilNets. 
(3) MZB filopodia can acquire Ags via multiple receptors 
(4) Low levels of Ag-induced BCR signaling cause the expansion of MZB FilNets so that the cells can scan for more Ag in order to become activated; high levels of Ag-induced BCR signaling cause retraction of the MZB FilNet as the cell prepares to divide and secrete antibodies. 
Finding from these studies could have broad implications for understanding how sensing/alerting cells are specialized to carry out their functions., program purpose french : Cells, organs, and organisms must respond to changes in their environment. The immune system is an excellent model of how sensing and alerting functions are integrated. Innate immune cells such as macrophages have receptors on their surface that capture pathogens, recognize microbial components as danger signals, and initiate immediate protective responses. If the infection is not cleared, T- and B-lymphocytes of the adaptive immune system are activated to generate more potent and specific responses (e.g. antibodies). Key intermediates are innate-like lymphocytes such as marginal zone B cells (MZBs), which detect pathogens, alert adaptive immune cells, and provide protection until the adaptive immune system is activated. 
MZBs reside at sites where the blood or lymph enters lymphoid organs. They express B cell receptors (BCR) that bind specific parts of foreign molecules (antigens [Ags]), as well as Toll-like receptors (TLRs) that bind microbial danger signals. The activation of MZBs by Ags and microbial components causes them to secrete antibodies that recognize broad classes of microbes. However, MZBs also play a key role in alerting other cells of the immune system. They capture Ags via the BCR and other receptors (CD21, CD36) on their surface. This allows them to promote the activation of T cells as well as circulating B cells that make highly specific antibodies. Although MZBs are important early responders, their cell biology has not been studied because they are few in number and no MZB cell lines exist. My lab has developed expertise in studying MZBs using single cell microscopy and our goal is to elucidate the mechanisms that allow them to be effective sensing/alerting cells. 
We found that MZBs rapidly extend a network of long, thin membrane protrusions called filopodia. This resembles the dendritic network of sensory neurons. We hypothesize that the MZB filopodial network (FilNet) is a sensory apparatus that is specialized for detecting microbes and acquiring Ags. The factors that regulate MZB FilNet formation are not known and its role as a sensory and Ag-acquisition apparatus has not been explored. 
The objectives of this proposal are to test the following hypotheses: 
(1) Sensory receptors (BCR, TLRs) and Ag acquisition receptors (BCRs, CD21, CD36) are present on MZB filopodia 
(2) Adhesion molecules, TLRs, hormones that MZBs are normally exposed to, and inflammatory mediators regulate the formation of MZB FilNets. 
(3) MZB filopodia can acquire Ags via multiple receptors 
(4) Low levels of Ag-induced BCR signaling cause the expansion of MZB FilNets so that the cells can scan for more Ag in order to become activated; high levels of Ag-induced BCR signaling cause retraction of the MZB FilNet as the cell prepares to divide and secrete antibodies. 
Finding from these studies could have broad implications for understanding how sensing/alerting cells are specialized to carry out their functions., agreement title english : The cell biology of marginal zone B cells: filopodial networks as an immune sensing apparatus, agreement title french : The cell biology of marginal zone B cells: filopodial networks as an immune sensing apparatus, agreement number : RGPIN, agreement value : 130000.0, 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