Unravelling the tissue-specific geography of protein aggregation in human disease

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Type 2 diabetes mellitus (T2DM) is a very common, chronic metabolic disorder characterised by high blood glucose, variable insulin resistance and insulin deficiency caused by loss of beta-cell function within pancreatic islets. Aggregation of the peptide hormone hIAPP (human islet amyloid polypeptide) in the pancreas is thought to contribute to beta-cell dysfunction and ultimately failure. hIAPP aggregates into amyloid fibrils via poorly characterized oligomeric species, in and around islets. More than 90% of people with T2DM have pancreatic hIAPP amyloid, but the link between these aggregates and loss of functional beta-cell mass is unclear. We do not currently know the structure of hIAPP amyloid that forms in the body, the precise chemical composition of aggregates, or the cellular components they interact with in and around beta-cells. Crucially, we do not understand how these factors change over time and space, e.g. whether there is a difference in aggregation near to islet microvasculature and if this is linked to the severity of the disease. We will establish a new collaboration between biologists, chemists, clinician scientists and engineers, using a nanopipette to perform localized extractions from human pancreatic tissue samples. This device has the resolution to sample from specific regions of individual cells, allowing us to survey and sample tissue cell-by-cell, assessing e.g. the number and/or structure of aggregates/oligomers in and around islets and their microvasculature. We then aim to establish methodologies to study aggregates extracted from tissue. We will use cryo-electron microscopy to investigate what the structure of these aggregates is and if it changes depending of where they are formed within the tissue. We will also employ mass spectrometry to understand what is the chemical composition of the aggregates and check if they interact with our molecules within the body.Crucially, our discoveries will be integrated into the Quality in Organ Donation (QUOD) biobank, adding all the knowledge we will generate within this project into their whole organ atlas for pancreas. We believe this is really important because it will facilitate the discovery of new mechanisms leading to T2DM and hopefully inform the scientific community on the way to prevent and treat this disease. Also we will be making our results available to the diabetes research community and engage with patients group to maximise the societal impact of our research.This project will therefore establish a new multi-modal, multi-centre team with national and international collaborators, aimed at delivering new molecular insight in diabetes research. It will allow us to integrate researchers with different expertise, but a common, shared goal to understand how, where and in what state hIAPP aggregation occurs in the beta-cells of patients with T2DM.