Grant: Project Grant

Chronic inflammatory diseases affect 82% of Canadians due to infection eg periodontitis, or autoimmunity eg arthritis. Infection is a health threat as antibiotic resistance rises. Understanding in vivo alterations in the extracellular matrix and inflammatory responses to infection, and the identification of key proteins or proteases is necessary to identify new drug targets. We discovered that inflammatory defense proteins are lost after they are cut by white blood cell proteases. This crucial discovery was possible with my innovative and highly advanced techniques known as degradomics-a method of uniquely identifying the cut ends of proteins by purifying them from the rest of the protein. As cuts are formed only during active disease, these segments are highly valuable as disease markers to develop new clinical tests and identify new drug targets. Retrograde infection of the placenta occurs via the cervix after amniotic membranes rupture. The time from membrane rupture to birth accurately documents the infection time from minutes to ~2 days at term to 1~14 days in prematurity. I will use degradomics to generate clinically relevant knowledge on how infection and immune proteases damage disease-fighting defense systems in human placenta ranging from undetected (subclinical) infection to severe chorioamnionitis. Thus, infection of human placenta is a unique system in which to study the step-by-step molecular events occurring in the infectious process without harm to the patient. Many common initial events in inflammation and infection are shared between diseases. Knowledge from studies in model tissue systems at early time points can be applied to other conditions affecting the skin, musculoskeletal system and oral cavity. Identifying cut protein ends will translate to developing new diagnostics for inflammatory diseases eg prematurity and identify the damaging proteases that can be targeted to improve health of Canadians and ensure sustainable health care costs.