Islet Amyloid Polypeptide (IAPP) is a 37 residue hormone that is co-secreted with insulin from the Beta cells of the pancreas. IAPP aggregation into amyloid fiber has been implicated in the death of insulin producing Beta cells in Type 2 Diabetes. The mechanisms of IAPP amyloid formation and toxicity are not well understood. Lipid bilayers are potent accelerants of amyloid formation. IAPP has been shown to cause membrane leakage, which is believed to be the source of cell toxicity. I propose to study these processes using small molecules that I have previously identified through a novel screening assay. These compounds'interference with the processes of amyloid formation and membrane leakage will lead to a better understanding of the mechanisms that govern these phenomena. First, small molecules will be characterized to determine the causes of the inhibition of amyloid formation. Lipid catalyzed and de novo (no lipid present) conditions will be used to distinguish between small molecules that specifically inhibit lipid catalysis and general amyloid inhibitors. CD will be used to monitor lipid binding and to identify changes in secondary structure due to small molecule interactions. NMR of 15N IAPP will be used to identify specific interactions between small molecules and IAPP. HSQC spectra will be used to identify individual residues perturbed by these interactions. By comparing NMR and CD data with kinetics, I will assign regions and residues that are important for amyloid formation and lipid binding. Second, I will use membrane leakage as a mimic for cell toxicity to identify compounds that are able to reduce the toxic effects of IAPP. Previous knowledge of the molecular interactions that give rise to amyloid formation and lipid binding will allow identification of the toxic species in amyloid formation, and potentially lead to new therapeutic targets for Type 2 Diabetes. IAPP is a small protein made in the pancreas, in the same cells as insulin. Aggregation of IAPP into amyloid fibers has been implicated in the death of these cells that make insulin in type 2 diabetes. Using small molecules I will investigate how IAPP aggregates and kills cells, as well as open new avenues for the treatment of type 2 diabetes.
| Saraogi, Ishu; Hebda, James A; Becerril, Jorge et al. (2010) Synthetic alpha-helix mimetics as agonists and antagonists of islet amyloid polypeptide aggregation. Angew Chem Int Ed Engl 49:736-9 |
| Hebda, James A; Saraogi, Ishu; Magzoub, Mazin et al. (2009) A peptidomimetic approach to targeting pre-amyloidogenic states in type II diabetes. Chem Biol 16:943-50 |
| Hebda, James A; Miranker, Andrew D (2009) The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes. Annu Rev Biophys 38:125-52 |
