Reference number : GC-2017-Q4-01192, amendment number : , agreement type : G, recipient legal name : Matsubara, Joanne (The University of British Columbia), recipient country : CA, recipient province : nan, recipient city : British Columbia|Colombie-Britannique, recipient postal code : nan, program name english : Engage Grants for universities, program name french : Subventions d'engagement partenarial pour les universités, program purpose english : The goal of the project is to identify the distribution of an important family of enzymes, the Granzymes, in the_x000D_
aging eye. Granzymes are serine proteases that were shown by our partner, ViDA Therapeutics, to play an_x000D_
important role in the abnormal degradation of extracellular proteins and tissue matrices in many parts of the_x000D_
body. To date, there are no studies on the role of Granzymes in the eye, an organ that contains an important_x000D_
extracellular structure called Bruch's Membrane (BM). As the eye ages, the extracellular matrix (ECM) within_x000D_
BM undergoes dramatic remodelling, hypothesized to lead to a dysfunctional blood-eye barrier. Recent studies_x000D_
have shown that loss of barrier function in the outer retina causes 1) retinal cell death, 2) pro-inflammatory_x000D_
events and 3) abnormal angiogenesis and vascular permeability._x000D_
The research proposed will provide relevant and novel information about the cellular distribution of_x000D_
Granzyme B in the aging eye that will allow us to understand Granzyme B's role in ECM remodeling. The_x000D_
hypothesis is that with aging, levels of Granzyme B increase in the choroidal tissues, leading to a compromised_x000D_
BM and concomitant loss of tight junctional proteins, dysregulated barrier function, increased vascular_x000D_
permeability, angiogenesis and pro-inflammation. Eye tissues from postmortem human donors (ranging from_x000D_
16yr to 80yrs of age) and wild type mice (C57Bl/6J, 3 to 18 months of age) will be assessed for longitudinal_x000D_
changes in protein levels of Granzyme B, cytokines (IL1b; IL1a), tight junctional proteins (ZO-1, cadherins),_x000D_
and angiogenic factors (VEGF, bFGF). Immunohistochemistry will identify the laminar distribution while_x000D_
antibody-based multiplexes will provide quantitative values (pg/mL) of these molecules in the retina. Optical_x000D_
imaging of the retina in Granzyme B knock-out mice and in aged mice treated with Granzyme B inhibitors will_x000D_
assess Granzyme B-induced changes in retinal structure in vivo. Key benefits include new target areas for_x000D_
partner's proprietary Granzyme B inhibitors. Future economic and social benefits include potential new_x000D_
treatments for Canadians suffering from chronic ocular inflammation., program purpose french : The goal of the project is to identify the distribution of an important family of enzymes, the Granzymes, in the_x000D_
aging eye. Granzymes are serine proteases that were shown by our partner, ViDA Therapeutics, to play an_x000D_
important role in the abnormal degradation of extracellular proteins and tissue matrices in many parts of the_x000D_
body. To date, there are no studies on the role of Granzymes in the eye, an organ that contains an important_x000D_
extracellular structure called Bruch's Membrane (BM). As the eye ages, the extracellular matrix (ECM) within_x000D_
BM undergoes dramatic remodelling, hypothesized to lead to a dysfunctional blood-eye barrier. Recent studies_x000D_
have shown that loss of barrier function in the outer retina causes 1) retinal cell death, 2) pro-inflammatory_x000D_
events and 3) abnormal angiogenesis and vascular permeability._x000D_
The research proposed will provide relevant and novel information about the cellular distribution of_x000D_
Granzyme B in the aging eye that will allow us to understand Granzyme B's role in ECM remodeling. The_x000D_
hypothesis is that with aging, levels of Granzyme B increase in the choroidal tissues, leading to a compromised_x000D_
BM and concomitant loss of tight junctional proteins, dysregulated barrier function, increased vascular_x000D_
permeability, angiogenesis and pro-inflammation. Eye tissues from postmortem human donors (ranging from_x000D_
16yr to 80yrs of age) and wild type mice (C57Bl/6J, 3 to 18 months of age) will be assessed for longitudinal_x000D_
changes in protein levels of Granzyme B, cytokines (IL1b; IL1a), tight junctional proteins (ZO-1, cadherins),_x000D_
and angiogenic factors (VEGF, bFGF). Immunohistochemistry will identify the laminar distribution while_x000D_
antibody-based multiplexes will provide quantitative values (pg/mL) of these molecules in the retina. Optical_x000D_
imaging of the retina in Granzyme B knock-out mice and in aged mice treated with Granzyme B inhibitors will_x000D_
assess Granzyme B-induced changes in retinal structure in vivo. Key benefits include new target areas for_x000D_
partner's proprietary Granzyme B inhibitors. Future economic and social benefits include potential new_x000D_
treatments for Canadians suffering from chronic ocular inflammation., agreement title english : Role of granzyme B in the aging retina, agreement title french : Role of granzyme B in the aging retina, agreement number : EGP, agreement value : 25000.0, agreement start date : 2018-03-07, 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 2018-2019)., additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier (2017-2018 à 2018-2019)., 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