• Login
    View Item 
    •   Home
    • Theses and Dissertations
    • Theses and Dissertations
    • View Item
    •   Home
    • Theses and Dissertations
    • Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of TUScholarShareCommunitiesDateAuthorsTitlesSubjectsGenresThis CollectionDateAuthorsTitlesSubjectsGenres

    My Account

    LoginRegister

    Help

    AboutPeoplePoliciesHelp for DepositorsData DepositFAQs

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Targeting Calcium-Calmodulin Binding to GRK5 in Cardiac Hypertrophy

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Coleman_temple_0225E_14138.pdf
    Size:
    1.000Mb
    Format:
    PDF
    Download
    Genre
    Thesis/Dissertation
    Date
    2020
    Author
    Coleman, Ryan
    Advisor
    Koch, Walter J
    Committee member
    Tilley, Douglas G.
    Elrod, John W.
    Sabri, Abdelkarim
    Schumacher-Bass, Sarah M.
    Department
    Biomedical Sciences
    Subject
    Cellular Biology
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/275
    
    Metadata
    Show full item record
    DOI
    http://dx.doi.org/10.34944/dspace/259
    Abstract
    Rationale: The pathogenesis and progression of pressure-overload heart failure (HF) encompasses aberrations in gene regulation, leading to maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. The trigger for maladaptation and HF is signaling through the G protein, Gq, and one downstream effector for this pathway is activation of non-canonical activity of G protein-coupled receptor kinase-5 (GRK5). This kinase, following hypertrophic stimuli, can translocate and accumulate in the nucleus of cardiomyocytes. The nuclear targeting of GRK5 is mediated by an amino-terminal (NT) domain that can bind calmodulin (CaM), which is required before its nuclear translocation. Objective: This study attempted to thwart GRK5-mediated pathology in pressure-overload maladaptation and HF by cardiomyocyte expression of a peptide encoding the NT of GRK5 (GRK5nt) that includes this CaM binding domain. Methods and Results: In vitro studies in myocytes showed that Gq-coupled receptor mediated hypertrophy was abrogated with GRK5nt expression and this included attenuation of pathological gene expression and NFAT activity. We confirmed that the GRK5nt binds to Ca2+-CaM, prevents its association with endogenous GRK5, and prevents its nuclear translocation. We generated cardiac-specific GRK5nt transgenic mice and showed in vivo that expression of this peptide prevents hypertrophic nuclear translocation of GRK5 and these mice exhibit significantly less cardiac hypertrophy, ventricular dysfunction, pulmonary congestion, and cardiac fibrosis following chronic transverse aortic constriction. Conclusions: Together our data support a role for GRK5nt as an inhibitor of pathological nuclear GRK5 signaling for HF prevention.
    ADA compliance
    For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
    Collections
    Theses and Dissertations

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Temple University Libraries | 1900 N. 13th Street | Philadelphia, PA 19122
    (215) 204-8212 | scholarshare@temple.edu
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.