Developing new therapeutic strategies for treating heart failure is dependent upon identifying molecular signaling pathways within the cardiac myocyte that are vulnerable to therapeutic exploitation. To date, our understanding of the regulators of myocyte contractility has been limited to the Frank-Starling law, the Bowditch effect, and intracellular signaling pathways. Myocyte shape, however, may serve as a distinct signal, capable of activating signaling pathways, genetic programs, and myofibrillar patterning. This proposal will address the role of myocyte shape in myofibrillogenesis and contractility. We propose that changes in myocyte shape can potentiate cytoskeletal architectures and myofibrillar patterning that can regulate contractile performance. To test this hypothesis, we will probe how myocytes respond to changes in myocyte shape and structure as controlled by the geometry of micropatterned islands of extracellular matrix proteins. Preliminary results suggest that the degree of myocyte spreading and the myocyte geometry can regulate the spatial distribution of sarcomeres and their serial and parallel bundling.
In Specific Aim 1, using multiple series of geometric islands to specifically vary projected myocyte area, perimeter, aspect ratio, and angular cues we will identify geometric parameters controlling this assembly. We will determine how the cytoskeleton self assembles and how myofibrils pattern in response to these signals and how their rates of assembly and patterning are affected.
In Specific Aim 2, we will look at how myocyte shape affects contractile strength, rate, and relaxation.
Specific Aim 3 will examine the role of myocyte shape, cytoskeletal architecture, and myofibrillar patterning in the Bowditch effect.
Specific Aim 4 examines the role of the small Rho GTPases Rac and Rho on myofibrillogenesis. These experiments will shed light on the role of the cardiac tissue microenvironment on cardiac morphogenesis and pathogenesis. ? ? ?
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