Grant: Project Grant

Our metabolism controls our health. The levels of glucose or vitamins or hormones in our blood tells us how well our body is functioning and errors in these levels can lead to diseases like diabetes. Measuring metabolite levels gives us a snapshot of our health - to do this we need an efficient way to measure and detect them. This is challenging since they are all quite different molecules. Our main way to 'see' metabolites is slow, needs very expensive, large machines in specialised facilities, and can only used by highly trained staff. We need a faster, cheaper, more accessible way to detect metabolites. We invented a method that can measure hundreds of metabolites in parallel using DNA sequencing, a powerful and accessible technology. Our method uses small sensors called Structure-Switching Aptamers (SSAs). Each SSA sees a unique target (e.g. glucose) and when it sees its target it releases a unique small piece of DNA, a 'barcode'. By sequencing the released barcodes we can tell which targets were present and at what levels. This works well but we need a SSA for every target we want to detect. The goal of this grant is to learn in as much depth how SSAs see their targets and how they distinguish between subtly different molecules so that we can generate accurate sensitive SSA sensors for every metabolite. We have 3 Aims: Aim 1: we will find the exact structures of a core set of SSAs and test how every possible change to their sequence affects their activity. This tells us precisely how these SSAs work. Aim 2: we test how making every possible sequence change of the core SSAs affects their ability to discriminate between closely related targets. Aim 3: We screen designed SSA libraries to search for sensors to ~3k different targets We believe our technology for measuring metabolites using DNA sequencing can transform how we detect these molecules in all areas of biotech and medicine - this grant will help us design and improve these sensors.