Mechanism of membrane-catalyzed amyloid formation in diabetes

University Of Wisconsin-Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): Type 2 diabetes is one of the most prevalent diseases in the US;approximately 20 million Americans have this disease. In Type 2 diabetes certain insulin-producing cells in the pancreas are impaired, leading to a loss of insulin production. A peptide known as amylin has been linked to Type 2 diabetes, and often forms amyloid fibers in patients with this disease. It has been speculated that amylin causes Type 2 diabetes through membrane-catalyzed amyloid formation. That is, amyloid is formed by peptides aggregating in association with cell membranes, and in the process the membranes are destroyed, impairing the cells. The aim of this proposed research is to understand the molecular mechanism of membrane-catalyzed amyloid formation, and to identify the cytotoxic peptide oligomers. A molecular understanding of these issues would lead to the development of pharmaceutical agents that could be used to block this process, providing more favorable outcomes for patients with this disease. The aim of this research will be accomplished through computer simulation of the conformations of the peptide monomer, dimer, and higher oligomers, and the free-energy barriers and pathways among these conformations, in the presence of model membranes. The calculations will be guided by very recent and ongoing state-of-the-art two-dimensional ultrafast vibrational spectroscopy experiments, which will shed light on the mechanism of the aggregation process. To make direct connection with these experiments, oligomeric peptide structures in membranes will be simulated, and theoretical two-dimensional vibrational spectra will be calculated. The comparison between theory and experiment will allow for the development of new hypotheses, and the suggestion of new experiments. This combined experimental/simulation/theoretical approach will reveal the molecular mechanism of membrane-catalyzed amyloid formation, and an understanding of how this process destroys cell membranes. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a major cause of death and debilitation in the US. The aim of the proposed research is to understand the origin of this disease, at the molecular level, with the expectation that the results of the research will play a part in its cure.