Grant: Project Grant

Significance-Inflammation is the body's normal protective response to infection and damage. Inflammation normally turns off to allow healing. Prolonged inflammation results in diseases e.g. gingivitis, periodontitis, arthritis and fibrosis. Gingivitis (mild gum inflammation) can progress to severe periodontitis to ultimately cause jaw bone and tooth 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 an increased risk of other serious conditions e.g. diabetes, heart attack and rheumatoid arthritis. Thus, prevention of periodontitis would also reduce the risk of associated diseases. Periodontitis develops slowly, with affected people often unaware as it is not yet possible to accurately diagnose active bursts of periodontal inflammation where irreversible damage occurs. Approach-Control of inflammation is complex and known to be fuelled by several proteins. Matrix metalloproteinases (MMPs) are enzymes that cut proteins to alter their functions, thus controlling the start and end of inflammation. With our unique methods that identify cut protein ends, we discovered that many pro-inflammatory proteins are cut by MMPs. Thus, by trimming inflammatory proteins and their regulators, MMPs orchestrate inflammation. We will study how cutting changes the actions of bioactive molecules in gingivitis, e.g. determine if trimming dampens or worsens inflammation and if male and female patients show differences that could influence treatment. We will make tools based on the cut ends to measure intact and cut molecules in healthy vs. inflamed human periodontium and will use these to assess if these cut ends can be used to monitor inflammation. Impact-Our study will help unravel new complexity in inflammation control in human tissues using gingivitis as a model. Our results will identify new drug targets and, in the future, potentially new tests for earlier diagnosis of inflammatory diseases.