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    Experimentally Altering the Compliance of Titin's Spring Region

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    Author
    Bull, Mathew Michael
    Issue Date
    2016
    Keywords
    HFpEF
    Hypertrophy
    Mechanotransduction
    RBM20
    Titin
    Physiological Sciences
    Alternative Splicing
    Advisor
    Granzier, Henk
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Chapter 1 of this work focuses on alternative splicing of titin as a proof of concept therapy for treating diastolic dysfunction and restrictive filling in a genetic murine model (Ttn^(ΔIAjxn)). The Ttn^(ΔIAjxn) mouse has increased strain on the spring region of titin and acts as a mechanical analogue of the titin-based increase in passive myocardial stiffness found in patients with heart failure and preserved ejection fraction (HFpEF). HFpEF is a complex disease characterized by diastolic dysfunction, exercise intolerance, and concentric hypertrophic remodeling. Approximately half all of heart failure patients suffer from diastolic dysfunction, however, no effective therapy exists for treating this pervasive syndrome. Titin, the largest known protein and molecular spring in the heart, has emerged as a prime candidate for therapeutic targets aimed at restoring compliance to the sarcomere in order to improve diastolic function. Titin has two main cardiac isoforms that are regulated by alternative splicing; the smaller N2B isoform (~3.0 MDa) and the larger more compliant N2BA isoform (~3.3 MDa). Diastolic stiffness of the left ventricle is dependent upon the N2BA:N2B isoform ratio. In the first half of this work, we modified these two primary isoforms by inhibiting the known titin splicing factor Rbm20. We demonstrate that Rbm20 reduction restores diastolic function, improves exercise tolerance and attenuates afterload induced pathologic remodeling of the left ventricle in Ttn^(ΔIAjxn) mice.The work in chapter 2 is focused on studies using the previously published N2B knock out (KO) murine model. The N2B spring element found in cardiac titin's I-band region has been proposed as a sensor and signaling "hot spot" in the sarcomere. This study investigates the role of titin's cardiac specific N2B element as a mechano-sensor for stress and strain induced remodeling of the heart. The N2B KO mouse was subjected to a variety of stressors including transverse aortic constriction (TAC), aortocaval fistula (ACF), chronic swimming, voluntary running and isoproterenol stimulation. Our data revealed that the N2B element is essential in preload stimulated cardiac hypertrophy as well as remodeling due to beta-adrenergic stress. Cardiac hypertrophy is a common maladaptive feature of heart failure patients and the mechanical triggers that determine pathologic growth are not well understood. My work in the N2B KO mouse reveal titin's important role in cardiac remodeling.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Physiological Sciences
    Degree Grantor
    University of Arizona
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