The heart senses the changing mechanical load and adjusts the contractile strength, on a beat-to-beat basis, to match the load in order to effectivel pump blood into circulation. High blood pressure often leads to arrhythmias and heart diseases. Defects in structural proteins, such as in muscular dystrophy, can also lead to cardiomyopathy. How do the cardiomyocytes sense and respond to mechanical forces? What molecules serve as mechanosensors? What are the signaling pathways that transduce mechanical stress to biochemical reactions in the cell? All these important questions need to be answered by investigating the mechano-chemo- transduction (MCT) mechanisms at cellular and molecular levels. A major hindrance to studying MCT mechanisms is a lack of technology to achieve two important capabilities: one is to control mechanical stress at the single cell level in 3-D environment mimicking the myocardium; the other is to tug on specific cell-surface mechanosensors during myocyte contraction in order to interrogate their role in MCT. However, all currently available techniques come short of having both capabilities. In this project, the PI and her interdisciplinary team will combine synthetic chemistry, muscle mechanics, and cellular and molecular biology to achieve two major goals: one is the bioengineering goal to develop an innovative `Cell-in-Gel' system that have the above two capabilities; the other is the scientific goal of using the new tools to investigate the MCT mechanisms during cardiomyocyte contraction under mechanical load. The Cell-in-Gel system has two major advantages over existing techniques (stretching cells using carbon fibers or glass rods). (1) Live cardiomyocytes are embedded in a 3-D hydrogel (elastic matrix composed of crosslinking polymers) so they experience 3-D mechanical stresses (longitudinal tension, transverse compression, shear stress) during contraction, mimicking the in vivo environment. (2) The gel chemistry allows tethering specific cell-surface mechanosensors (e.g. dystroglycans, integrins) to the gel matrix to impose mechanical stress on them during cell contraction. The Cell-in-Gel system will enable scientists to study MCT complexes, their downstream signaling, and functional consequences in live cardiomyocytes and other cell types. We will test the central hypothesis that two major MCT complexes in cardiomyocytes-the dystrophin-glycoprotein complex (DGC) and the vinculin-talin-integrin complex (VTI)- transduce mechanical stress to modulate the Ca2+ signaling system on a beat-to-beat basis, which enhances Ca2+ transient and contractility in response to mechanical load, but this same mechanism can also cause Ca2+ dysregulation under excessive load. Resolving this MCT mechanism is fundamental to understanding how the heart responds to mechanical load to autoregulate contractility, how excessive loads cause heart diseases, and how DGC mutations in muscular dystrophy lead to Ca2+ dysregulation and cardiac dysfunction.
In the heart, cardiac muscle not only produces force to pump blood but also responds to mechanical stresses. The overall goal of this project is to develop and engineer a novel `Cell-in-Gel' system to control mechanical stress at single cell and molecular levels. This new technology will enable scientists to investigate how the cells in the heart sense and respond to mechanical forces? What molecules serve as mechanosensors? What are the mechano-chemo-transduction pathways that transduce mechanical force to biochemical reactions in the cell? The answers to these questions are needed for identifying molecular targets for developing drug therapies. Therefore, the proposed are important and necessary for developing drugs to treat mechanical stress-induced heart diseases such as high blood pressure induced arrhythmias and heart failure, muscular dystrophy related cardiac dysfunction, and dilated cardiomyopathy.
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| Chen-Izu, Ye; Izu, Leighton T (2017) Mechano-chemo-transduction in cardiac myocytes. J Physiol 595:3949-3958 |
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| Chiamvimonvat, Nipavan; Chen-Izu, Ye; Clancy, Colleen E et al. (2017) Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics. J Physiol 595:2229-2252 |
| Grandi, Eleonora; Sanguinetti, Michael C; Bartos, Daniel C et al. (2017) Potassium channels in the heart: structure, function and regulation. J Physiol 595:2209-2228 |
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