Membrane Interaction and Membrane Mediated Aggregation of Amylin

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): The impact of Type II diabetes disease is increasing with the expanding percentage of the elderly within our population. Therefore there is an urgent need for medical procedures to cure this disease. Type II diabetes develops due to a combination of decreased insulin secretion and a decrease in the body's response towards insulin. A key factor in the development of Type II diabetes is the loss of insulin producing beta-cells. The membrane interactions, misfolding and aggregation of human Islet Amyloid Polypeptide (hIAPP) is believed to play crucial roles in this process. Previous studies have shown that hIAPP forms small aggregates that kill beta-cells by disrupting the cellular membrane. However, it is not known exactly what causes this process, how hIAPP disrupts the cell's membrane, and, most importantly, how it can be stopped. In this study we propose to use solid-state NMR spectroscopy and other biophysical techniques to address these questions. We will use fluorescence experiments to understand the kinetics of hIAPP aggregation and to determine the conditions for high-resolution studies using solid-state NMR spectroscopy. Solid-state NMR studies will provide insights into the catalytic role of membranes on the formation of misfolded and toxic forms of hIAPP, and the process of membrane-disruption by hIAPP. This information will be essential to understand what makes some individuals susceptible to Type II diabetes and why Type II diabetes strikes late in life. In addition, solving the high-resolution structure of hIAPP in physiologically-relevant membranes using solid-state NMR techniques will answer why some forms of IAPP (such as the human form) are toxic and others (such as the rat form) with very similar sequences are not. These high-resolution structures will guide the development of drugs to stop the loss of insulin production because of beta cell death. Although the proposed study is focused on hIAPP, the outcome will be of importance to other aging-related diseases such as Alzheimer's disease and Parkinson's disease. PUBLIC HEALTH RELEVANCE: Type II diabetes develops due to a combination of decreased insulin secretion and a decrease in the body's response towards insulin. A key factor in the development of Type II diabetes is the loss of insulin producing beta-cells. The proposed studies will give an understanding of the mechanism of how beta-cells are killed by IAPP and may serve to guide the design of drugs to block the toxic effect of IAPP on insulin producing beta-cells.