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  1. Article ; Online: 3158 Sunitinib-Induced Cardiotoxicity in an Engineered Cardiac Microtissue Model

    Carissa Livingston / Abhinay Ramachandran / Elise Corbin / Alexia Vite / Alexander Bennett / Kenneth Margulies

    Journal of Clinical and Translational Science, Vol 3, Pp 114-

    2019  Volume 115

    Abstract: OBJECTIVES/SPECIFIC AIMS: The aims of this study are threefold. Firstly, we are examining the effects of increased in vitro afterload (a proxy for hypertension) on human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) response to sunitinib in a ... ...

    Abstract OBJECTIVES/SPECIFIC AIMS: The aims of this study are threefold. Firstly, we are examining the effects of increased in vitro afterload (a proxy for hypertension) on human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) response to sunitinib in a durable and dynamic cardiac microtissue culture system. Secondly, we are exploring effects of repeat exposure and recovery of both sunitinib and afterload throughout the lifetime of the hiPSC-CM microtissue. Finally, we are assessing methods to prevent and treat sunitinib induced cardiotoxicity. Primary outcomes for this study are commonly utilized metrics of cardiotoxicity: degree of caspase activation, electrophysiology benchmarks for minimum voltage threshold and maximum capture rate, and microtissue force generation. METHODS/STUDY POPULATION: HiPSC-CMs are cultured and matured as 3D cardiac microtissues (CMTs) on a microtissue array. After maturation, cells are exposed to sunitinib doses of 0µM, 0.5µM, 1µM or 5µM for 12 hours. Concurrently with sunitinib dosing, increases in microtissue array stiffness are created with application of an external magnetic field. Afterload spring constants are fixed at pre-determined physiologic values ranging from 0.5µN/µm, to 5µN/µm. For Aim 1: Half of the CMTs are harvested at 8 hours after sunitinib dosing to conduct the caspase 3/7 assay, and the remainder are examined for 3 days following drug exposure to track temporal changes in electrophysiology and force generation. For Aim 2: After CMT maturation, 12-hour exposures to sunitinib are repeated three times at a fixed dose, with doses separated by one week. Concurrently with sunitinib dosing, increases or decreases in microtissue stiffness are created by changing the strength of an applied external magnetic field to create “ramp up” or “ramp down” stiffness conditions. Caspase assay and contractility metrics are measured at each timepoint. For Aim 3: Experimental conditions are conducted as described in Aim 1. Prior to the introduction of sunitinib, either carvedilol or an ...
    Keywords Medicine ; R
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Cambridge University Press
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: 3299 Dynamic Afterload Cardiac Microtissue Model To Examine Molecular Pathways of Heart Failure

    Abhinay Ramachandran / Carissa Livingston / Elise Corbin / Alexia Vite / Alex Bennett / Kenneth Margulies

    Journal of Clinical and Translational Science, Vol 3, Pp 9-

    2019  Volume 9

    Abstract: OBJECTIVES/SPECIFIC AIMS: This project aims to determine the key molecular pathways that link increased myocardial wall stress to cardiomyocyte hypertrophy and subsequent heart failure. We will use a cardiac microtissue (CMT) model with dynamically ... ...

    Abstract OBJECTIVES/SPECIFIC AIMS: This project aims to determine the key molecular pathways that link increased myocardial wall stress to cardiomyocyte hypertrophy and subsequent heart failure. We will use a cardiac microtissue (CMT) model with dynamically tunable cantilever stiffness to examine changes in CMT hypertrophy and electro-mechanical properties in response to increased afterload (cantilever stiffness). Subsequently, we will determine if inhibition of pro-hypertrophic or anti-hypertrophic pathways alter the hypertrophic response to increased afterload. Primary outcomes for this study are static/dynamic force, minimum electric field strength (VT), maximum capture rate (MCR), average cell area, and tissue cross-sectional thickness, and secondary outcomes are degree of myoblast activation and apoptosis. METHODS/STUDY POPULATION: CMT platforms will be fabricated using iron-doped polydimethylsiloxane (PDMS) to create magnetically tunable cantilevers. Cantilever stiffness will be increased with the application of an external magnetic field. Cantilever stiffness will be measured using a capacitance probe, where the force required to deflect both the cantilever and calibration probe is in accordance with Hooke’s Law. Human induced pluripotent stem cell cardiomyocyte (hiPSC-CMs) will be cultured and matured as 3D CMTs. In-vitro static/dynamic force generation will also be calculated by measuring the deflection of the cantilevers and applying Hooke’s law. CMTs will be paced using carbon electrodes to obtain VT and MCR. Structural data will be obtained using immunostaining and confocal microscopy. Finally, we will use pharmacologic inhibitors to inhibit molecular pathways that we identified in prior genetic screens such as ABCC8 (anti-hypertrophic mediator) and C1QTNF9 (pro-hypertrophic mediator). We will examine each of these pathways in low- and high-stiffness conditions. RESULTS/ANTICIPATED RESULTS: We believe increased afterload will cause significant hypertrophy, measured by increases in CMT cross-sectional ...
    Keywords Medicine ; R
    Subject code 621
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Cambridge University Press
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

    More links

    Kategorien

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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