Biophysical Studies of Amyloid Formation by Polypeptide Hormones

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PROJECT SUMMARY This application describes an interdisciplinary program designed to study amyloid formation by human islet amyloid polypeptide (hIAPP, also known as amylin), the causative agent of pancreatic islet amyloidosis-induced beta-cell toxicity in diabetes. Amyloid formation by hIAPP is a well-established pathological factor contributing to the development of type 2 diabetes, a debilitating disease that has reached epidemic proportions in the United States. Islet amyloidosis is also a major contributor to islet cell transplantation failure. Aggregation of hIAPP has recently been implicated in islet beta-cell deficiency in type 1 diabetes, and in the downstream cardiovascular complications of diabetes. hIAPP is normally secreted as a soluble polypeptide hormone together with insulin from the pancreatic beta-cells and plays an adaptive role in glucose metabolism, including the regulation of the action of insulin and other pancreatic metabolic hormones. However, in metabolic disease, hIAPP aggregates into cytotoxic conformations that assemble into amyloid fibrils that deposit as plaques in the islets. The process of islet amyloid formation is toxic to beta-cells and plays an important role in disease progression. Wild type hIAPP is responsible for islet amyloidosis in the majority of individuals, but an S20G mutation is linked to an increased risk of diabetes. Soluble analogs of hIAPP are of interest as adjuncts to insulin therapy for the treatment of diabetes, particularly for type 1 diabetes, where the rapid loss of beta-cells results in dependence on hormone replacement therapy. Soluble hIAPP analogs are also of interest for the potential treatment of obesity. The planned studies address fundamental issues in amyloid formation, and will offer important insight into strategies for the treatment of type 1 and type 2 diabetes. We will apply an interdisciplinary combination of protein biophysics, biochemistry, and islet cell biology to address three key issues in the field: 1) defining the determinates of hIAPP amyloid formation and toxicity, including the role of specific amino acid sidechain interactions; 2) elucidating the reasons for the aggressive aggregation and heightened toxicity of the S20G mutant of hIAPP; and 3) the rational development and rigorous testing of next generation soluble analogs of hIAPP. The studies will define the molecular features impacting hIAPP amyloid formation and islet beta-cell toxicity. They will identify general principles that will be broadly applicable to other protein aggregation diseases, and to mechanistic studies of amyloid formation.