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Metadata Commons Identifier

HMC000134

Project Title

Developing Topical Formulations of Natural, Plant-derived Granzyme B Inhibitors for the Treatment of Pressure Injuries

Project Description

RATIONALE: Pressure injuries (PIs) are areas of localized damage to the skin and/or underlying tissues. They are the most prevalent wound in the healthcare setting with 26% of patients in acute or non-acute settings exhibiting a pressure injury. PIs often recur and irreversible PIs can be developed as quickly as 20 minutes in frail or insensate people. With increased wait times and nurse shortages in hospitals, novel therapeutic solutions for early intervention are in dire need.INNOVATION: Granzyme B (GzmB) is a serine protease that is elevated in aging human skin and chronic, non-healing wounds such as PIs. Genetic deletion or pharmacologic inhibition of GzmB improved collagen remodeling, wound healing, and tensile strength of wounds in mouse models of pressure injury and other tissue injury (diabetic wounds, burn wounds, aneurysm, and UV-induced damage). Our team has identified 3 Health Canada-approved, natural, plant-derived compounds that are safe and inhibit the proteolytic activity of GzmB. Herein, we propose to characterize the mechanisms of the natural compounds, synthesize novel gel formulations, and evaluate the efficacy of the natural GzmB inhibitors in a mouse model of pressure injury. As these compounds are Health Canada-approved natural health product ingredients, translation into the clinic would be expedited and more economically feasible.HYPOTHESIS: Topical application of natural plant-derived compounds to pressure wounds will inhibit Granzyme B-mediated extracellular matrix degradation, facilitating positive tissue remodeling.ACTIVITY 1 – To globally profile GzmB substrates in patient PI fluids. With Sector Partners Vancouver Coastal Health and viDA Therapeutics, as well as Collaborator Dr. Colin Collins, we will be using terminal amine isotopic labeling of substrates (TAILS), a quantitative proteomics methodology, to identify novel GzmB substrates in patient pressure wound fluids. This study will allow us to uncover underlying mechanisms as well as potential biomarkers for wound severity and GzmB treatment response.ACTIVITY 2 – To assess efficacy of natural GzmB inhibitors in a mouse model of pressure injury in aging skin. With a medicinal chemist, we will derive novel gel formulations of natural GzmB inhibitors. Using an established in vivo mouse model of PIs, with which our team has extensive experience, we will test the topical gel formulations and quantify GzmB activity/substrate levels, injury severity, wound healing, inflammation, markers of remodeling, and tensile strength. Genome BC Project ID: GEN057

Project Funder(s)

Genome British Columbia, Vancouver Coastal Health (VCH), viDA Therapeutics Inc

Project Institution(s)

University of British Columbia (UBC)

Project Investigator(s)

David Granville, Heather Mak

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Keywords

granzymes, serine proteases, pressure injuries, wound healing, natural inhibitors, proteolytic activity, ELISAs, proteomics, mass spectrometry, wound healing

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Study Completed

Post to REACH BC Platform

Cohort Name

Pressure Injuries Patient Cohort

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decubitus ulcer

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