Mechanistic Studies and Inhibition of Islet Amyloid

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A number of debilitating human diseases involve the association and aggregation of normally soluble proteins to form insoluble deposits known as amyloid. Amyloid, or the process of its formation is toxic and has been implicated in more than twenty human disorders ranging from neurodegenerative diseases such as Parkinson disease, Huntington?s disease, and Alzheimer?s disease to type-2 diabetes. The research outlined here focuses on a protein known as Islet Amyloid Polypeptide (IAPP, also known as Amylin). IAPP is a hormone which is released from the pancreatic beta-cells together with insulin. IAPP normally acts as a partner with insulin, but forms amyloid deposits in type-2 diabetes. The deposits are localized in the pancreases, are toxic to the insulin producing pancreatic beta-cells, and play a role in the pathology of the disease by killing beta-cells. There is growing evidence that amyloid formation by IAPP is also a critical factor in the failure of islet cell transplants. Type-2 diabetes is reaching epidemic proportions in the UK, but comparatively little is known about amyloid formation by IAPP. A combination of protein chemistry, biochemistry, cell biology and new biophysical approaches will be used to study amyloid formation by IAPP and its consequences. The work involves the application of new techniques for studying the intermediate steps in the process of amyloid formation. A key goal is to define the process in as much detail as possible since a detailed understanding of amyloid formation is critical for drug development. These studies will be complimented by the development of new inhibitors of IAPP amyloid formation and by the demonstration of new strategies for screening libraries of chemical compounds for potential inhibitors. IAPP is an important protein for study in its own right, but it is also an excellent model system for studies of amyloid formation by other proteins, including proteins involved in neurodegenerative disorders. Outreach to undergraduates, pre-university students, and the general public will involve lectures, lab visits (open days), and the hosting of ?lab experiences? for younger students.