Grant: Undergraduate: Summer Studentship Award - Institute Community Support

Matrix metalloproteinase 1 (MMP1) is the founding member of the MMP family of 23 enzymes that can cut up extracellular matrix (tissue surrounding cells and blood vessels). MMP1 unwinds and cuts triple helical collagen that is resistant to cleavage by other enzymes. Its extracellular matrix degrading capability implicates MMP1 as detrimental in diseases like arthritis, gum disease and cancer. Other MMPs have beneficial as well as detrimental functions, like bringing white blood cells into tissues when needed to fight infection. Trying to block cancer spread with MMP inhibitor drugs caused side effects-MMP inhibitors tend to block multiple MMPs and can prevent essential and beneficial processes in patients, as well as the targeted process. A few non-matrix substrates are known for MMP1, suggesting that this protease is also involved in processing and regulation of other bioactive proteins. The Overall lab has developed specialised proteomics techniques to identify proteins that are cut (substrates) by MMPs. We have thus identified many new non-matrix substrates of other members of the MMP family, including proteins that have important biological roles in inflammation and immunity. We will incubate tissue fibroblast cells with or without MMP1 and collect proteomes (secreted proteins, or cell surface proteins). Using our TAILS method, we will label the samples with different labels and isolate the cut peptides. Then by mass spectrometry, we will identify which proteins are cut by MMP1 and where. We will then study some of newly identified MMP1 substrates to determine the effect that cutting has on their function. Using the techniques that are now well established in the Overall lab, we will gain insight into the full range of MMP1 substrates to give us a better picture of the functions of MMP1. We may be able to find better targets for the treatment of arthritis by targeting specific substrates and pathways downstream of MMP1 rather than by inhibiting MMP1 itself.