Grant: Project Grant

Significance-Inflammation is the body's normal protective response to infection and damage that turns off after healing. Prolonged or abnormal inflammation results in diseases such as gingivitis, periodontitis, arthritis and sepsis. Gingivitis (mild gum inflammation) can progress to periodontitis (severe gum inflammation) that ultimately causes tooth and bone loss. Periodontal disease is common-in the US 47% of adults >30 years have gum disease, rising to 70% at >65 years-and is associated with increased risk of other more serious conditions eg diabetes, heart attack, and rheumatoid arthritis. Periodontitis typically develops slowly and many affected people are unaware. Sadly, it is not yet possible to diagnose active bursts of periodontal inflammation where irreversible damage occurs. Of note, prevention of periodontitis would reduce the risk of associated diseases. Approach-The inflammatory process is poorly understood. A protein known to fuel inflammation is HMGB1. Matrix metalloproteinases (MMPs), enzymes that cut various proteins to alter their functions, control aspects of inflammation by trimming inflammatory proteins. With our unique techniques that identify cut protein ends, we discovered that HMGB1 is cut by MMPs. Here we will study how MMP cutting affects HMGB1 action in inflammation, eg determine if trimming dampens or worsens inflammation. We will make tools based on the HMGB1 cut ends to measure intact and cut HMGB1 in healthy and inflamed human tissues, and will use the tools to assess whether HMGB1 cut ends can be used to monitor inflammation. Impact-Our study will help us unravel new complexity in inflammation control and aid the design of tests for early signs of inflammation and better treatments, not only for accurate diagnosis of periodontitis, but also other inflammatory conditions such as arthritis and sepsis that affect millions of Canadians. This will improve health outcomes, increase quality of life, survival and reduce healthcare costs.