The molecular basis of islet amyloid induced beta-cell death and the inhibition of islet amyloid induced toxicity (360G-Wellcome-107927_Z_15_Z)
Amyloid formation plays a central role in a wide range of devastating diseases, but the mechanism of amyloid formation has yet to be defined in detail for any protein. The nature of the toxic species produced during amyloid formation is controversial and efforts at drug development have been disappointing. This proposal exploits new approaches, developed in our laboratory, to address these critical issues. Our work is focused on islet amyloidosis by the neuropancreatic hormone islet amyloid polypeptide (IAPP, also known as Amylin) and its role in type-2 diabetes (T2D) and beta cell death. Key questions are: (1) What is the mechanism of IAPP amyloid formation?(2) What are the properties of the toxic oligomers produced during islet amyloidosis? (3) What distinguishes toxic from non-toxic oligomers and what factors correlate with toxicity? (4) Why do some amyloid inhibitors protect against toxicity while other promote it? Answering these questions is central to an understanding of amyloidosis and to developing effective therapeutic strategies.
£1,732,599 07 Jul 2015