Understanding protein aggregation in human pancreatic tissue

Type 2 diabetes (T2D) is a chronic disorder, characterised by high blood glucose, resistance to insulin, and loss of pancreatic β-cells. T2D constitutes a major societal concern, with ~5m people in the UK living with T2D, at an annual economic cost to the NHS of >£10 billion.

Aggregation of the peptide hormone hIAPP (human islet amyloid polypeptide) in the pancreas is thought to contribute to β-cell dysfunction and ultimately to failure, but how and where hIAPP aggregates into amyloid fibrils is poorly characterized, both in diabetes but crucially also in the healthy pancreas. E.g. we do not currently know the structure of hIAPP oligomers, or the precise structure/composition of hIAPP aggregates in vivo, or the cellular components aggregates interact with in and around β-cells. Crucially, we do not understand how these factors change with time and space – for instance whether there is a difference in aggregation near to islet microvasculature.

This studentship would focus on using light microscopy to image hIAPP in donated human pancreatic tissue, and focused ion beam scanning electron microscopes (FIB-SEM), to mill pancreatic tissue using an ion beam. Two types of FIB milling are relevant: (1) block face milling to understand pancreatic structure at high resolution and identify amyloid deposits in situ for the first time, and (2) milling ‘lamellae’ that capture amyloid deposits that will be studied using cryo-electron tomography (cryoET). Our ultimate goal is to understand the molecular structure and distribution of amyloid in pancreas to near-atomic resolution using sub-tomogram averaging. To facilitate this we will also solve the structure of amyloid fibrils extracted from tissue using single particle cryoEM. The long term aim is to use such structural information to design and characterise new molecules that can disrupt hIAPP aggregation and understand their effects on pancreas function.