• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Molecular mechanisms of neuroprotection by the herpes simplex virus type 2 gene ICP10PK

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Find Full text
    Author
    Wales, Samantha Q.
    Advisor
    Aurelian, Laure
    Date
    2008
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    Recent progress in molecular biology has focused interest on gene therapy as a strategy for the control of chronic and acute neurodegenerative disorders. However, the selection of the appropriate gene and delivery vector is a clinical challenge. Herpes simplex virus type 2 (HSV-2) is a promising gene delivery vector, as it is neurotropic, has a large genome that is amenable to genetic manipulation, and unlike HSV-1, it does not cause encephalitis in adult humans. HSV-2 contains an anti-apoptotic serine/threonine protein kinase (known as ICP10PK), that acts as a constitutively activated growth factor receptor. It activates Ras and its downstream MEK/ERK survival pathway and inhibits apoptosis caused by virus infection of primary hippocampal cultures (Perkins et al. 2003b, Perkins et al. 2002a). The studies described in this report were designed to examine the molecular mechanisms of ICP10PK-mediated neuroprotection, and ensure that it can act independently of other viral proteins. Rat pheochromocytoma (PC12) cells stably transfected with ICP10PK (PC47 and PC70 cells) or its kinase-negative mutant p139(TM) (PC139 cells), were neuronally differentiated by culture with nerve growth factor (NGF) and examined for cell survival after NGF withdrawal. Apoptosis was seen in PC12 and PC139, but not PC47 and PC70 cells. In PC47 cells, neuroprotection was MEK- and PKA-dependent, associated with stabilization/activation of the transcription factor cAMP-responsive element binding protein (CREB), inhibition (phosphorylation) of the pro-apoptotic protein Bad and stabilization of the anti-apoptotic proteins Bcl-2 and Bag-1. In PC70 cells, neuroprotection occurred downstream of caspase activation, and involved MEK-dependent up-regulation of the anti-apoptotic protein XIAP and down-regulation of the XIAP inhibitor Smac/DIABLO. To examine whether ICP10PK is also neuroprotective in other paradigms, we examined its effect in an in vitro model of Parkinson's disease, using the neurotoxin MPP+. ICP10PK, but not p139(TM), inhibited MPP +-induced programmed cell death through inhibition of calpain-dependent Bax translocation to the mitochondria, AIF nuclear translocation, and caspase activation, indicating that the actions of ICP10PK are kinase-dependent. Collectively, the data indicate that ICP10PK has broad-spectrum neuroprotective activity that extends beyond apoptotic cellular programs. Further study of its use as a gene therapy strategy is warranted.
    Description
    University of Maryland, Baltimore. Pharmacology and Experimental Therapeutics. Ph.D. 2008
    Keyword
    Biology, Molecular
    Biology, Neuroscience
    Biology, Cell
    ICP10PK
    Genetic Therapy
    Genetic Vectors
    Herpesvirus 2, Human
    Neurodegenerative Diseases--therapy
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/971
    Collections
    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

    entitlement

     
    DSpace software (copyright © 2002 - 2021)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    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.