The amyloid oligomers are sticky molecules that attach to cellular membranes and change their mechanical and electrical properties, thus generating molecular forces that can alter cellular signal transduction, function and viability. Despite sustained research efforts, the biomechanics of amyloid oligomer-cell interaction remains elusive. The major goal of this project is to assess the biomechanics of the interaction of islet amyloid polypeptide (IAPP) oligomers with cardiac myocytes, the beating heart cells. IAPP oligomers form within pancreatic Ã¢-cells in patients with obesity and type-2 diabetes and are then released in the blood along with insulin. They can deposit locally in pancreatic islets and also in peripheral organs, including the heart. Cardiac accumulation of IAPP amyloids contributes to the development of heart dysfunction, the number one killer in obesity and diabetes. Due to the complex nature of the molecular forces acting at the IAPP oligomer-cardiac myocyte interface, various interaction modes and cellular responses can be expected. Major questions to be addressed in the proposed research are as follows: (1) do IAPP oligomers a) attach to and grow into fibrils at the sarcolemma, b) create pores or c) enter cardiac myocytes?; (2) what are the effects on the sarcolemmal processes?, (3) how they affect contractility and viability of the cardiac myocyte? These questions will be addressed in a multidisciplinary research project that combines biomechanical principles and methods with modern cell physiology experiments, innovative transgenic animal models and mathematical modeling. Deciphering the molecular and cellular signature of IAPP amyloid oligomers in the heart can have a long-term impact in the diagnosis and treatment of diabetic heart dysfunction, a large and growing epidemic with enormous health care costs and social consequences. The expected results may also represent a significant advancement in studying other generic amyloid oligomer-cell interactions, i.e. AÃ¢ oligomers and polyglutamine oligomers interacting with neurons and astrocytes.