Biomechanics of Amyloid Oligomer-Induced Stress on Cardiomyocytes

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 islet amyloid polypeptide (IAPP) oligomer interaction with cardiomyocytes, the beating heart cells. IAPP oligomers form within pancreatic â-cells in patients with obesity and type-2 diabetes and are then released in the blood along with insulin. IAPP makes up the amyloid deposit in pancreatic islets, the hallmark of type-2 diabetes. Research in our laboratory showed the presence of IAPP amyloid oligomers in blood and failing hearts from patients with obesity and type-2 diabetes and demonstrated their cardiotoxicity in an animal model. Due to the complex nature of the molecular forces acting at the IAPP oligomer-cardiomyocyte 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 cardiomyocytes?; (2) what are the effects on the sarcolemmal processes?, (3) how they affect contractility and viability of the cardiomyocyte? 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. The planned work will uncover the primary structural defect induced by IAPP oligomers in the sarcolemma and downstream alterations of Ca cycling, contractility and viability of the cardiomyocytes. The results will help us understand how cardiomyocytes respond mechanically to amyloid oligomer-induced stress. This will drive future studies on how the interaction with amyloid oligomers may affect kinase cascades, gene expression and metabolism in cardiomyocytes. The intellectual merit: The biomechanism underlying the IAPP oligomer-mediated alterations of cardiomyocyte structure and function is not known. The proposed research integrates engineering and life science principles and methods to elucidate this pressing biomedical problem. 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. Aâ oligomers and polyglutamine oligomers interacting with neurons and astrocytes. Because the amyloid oligomers are pathogenic, they were almost exclusively regarded as of biological and pathological interest. However, the oligomer-cell interaction is an intriguing problem of cellular biomechanics that may offer a new angle on how cells respond, remodel their architecture and adapt to critical mechanical stress. The planned research is innovative in using cellular biomechanics principles and methods to address the IAPP oligomer-cardiomyocyte interaction. The research team has complementary and integrated expertise in cellular biomechanics and heart physiology and will benefit from a rich scientific environment with great expertise in this field at the University of Kentucky in Lexington. The broader impacts: The proposed project advances both engineering and life sciences. It addresses, through an innovative cellular biomechanics approach, how cardiomyocytes respond mechanically to the amyloid oligomer-induced stress, which relates to both an important basic science question and to a pressing biomedical problem. The inherently interdisciplinary nature of this research will provide graduate students interacting with the research team with exceptional training in both engineering and life sciences. The PI teaches both at graduate and undergraduate levels. Funds for the present research project will provide opportunities for undergraduate and graduate students, including gifted minority students from Lexington area, to complete research internships in the field of cellular biomechanics.