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Jiayang Li Thesis revised v2.pdf (3.94 MB)

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EXAMINING THE EFFICACY OF MYBPC BASED THERAPIES IN MOUSE MODELS OF CARDIOMYOPATHIES

Li, Jiayang
http://rave.ohiolink.edu/etdc/view?acc_num=case1565375410627607

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Disruption of the tightly regulated processes of myofilament contraction and relaxation often leads to cardiovascular dysfunction and progressive heart failure-related morbidity and mortality. Perturbed myofilament contractility in either direction is associated with pathologic hypertrophy. In general, mutations that activate the sarcomere result in hypercontractile myofilament function and cardiac diastolic dysfunction that frequently cause hypertrophic cardiomyopathy. Mutations that cause loss of sarcomeric function result in hypocontractile myofilament function and cardiac systolic dysfunction. However, it is unknown if contractility corrective therapy can provide protective benefit from developing pathologic remodeling and heart failure. This thesis examined the mechanisms of cardiac myosin binding protein C (MyBPC) mediated myofilament contractility modulation in mouse models of dilated and hypertrophic cardiomyopathy. MyBPC is a thick filament protein that regulates myocardial contractility through interactions with the myosin motor domain and the actin thin filament. This work used a combination of transgenic and gene transfer approaches to examine the impact of MyBPC modulation on DCM and HCM progression, assessed by a combination of echocardiography and pressure-volume analysis to study in vivo cardiac function and steady-state and dynamic skinned fiber experiments to study in vitro myofilament function. First, we generated transgenic mice with homozygous loss of function of MLP and MyBPC genes. MLP-/- mice exhibit decreased systolic contractility and develop DCM. The ablation of MyBPC in MLP-/- mice significantly enhanced systolic ventricular pressure development and prevented ventricular dilation. These results demonstrate that carriers of mutations that cause depressed contractile function can potentially benefit from MyBPC mediated contractile activation. Next, I examined the effect of AAV9 gene transfer of full length (FL) MyBPC and MyBPC N-terminal fragment C0C2 cDNA in MyBPC-/- mice. The absence of MyBPC in MyBPC-/- mice causes increased myofilament kinetics and development of HCM. The FL protein rescued myofilament function and prevented pathologic remodeling. I found, for the first time, C0C2 had a similar effect, which also restored cross-bridge kinetics, improved ventricular function, and largely prevented pathologic remodeling, demonstrating the N-terminal domain is sufficient in mediating MyBPC regulatory effects. Overall, this work has shown that MyBPC based contractile modulation can restore homeostatic contractile function and decrease cardiomyopathy susceptibility.
George Dubyak (Committee Chair)
Julian Stelzer (Advisor)
William Schilling (Committee Member)
Brian Hoit (Committee Member)
Isabelle Deschenes (Committee Member)
217 p.
Physiology

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Citations

  • Li, J. (2019). EXAMINING THE EFFICACY OF MYBPC BASED THERAPIES IN MOUSE MODELS OF CARDIOMYOPATHIES [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1565375410627607

    APA Style (7th edition)

  • Li, Jiayang. EXAMINING THE EFFICACY OF MYBPC BASED THERAPIES IN MOUSE MODELS OF CARDIOMYOPATHIES. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1565375410627607.

    MLA Style (8th edition)

  • Li, Jiayang. "EXAMINING THE EFFICACY OF MYBPC BASED THERAPIES IN MOUSE MODELS OF CARDIOMYOPATHIES." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1565375410627607

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.