• 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

    Genetic and Functional Characterization of Zonulin as Prehaptoglobin-2 and its Role in Inflammation and Autoimmunity

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Sturgeon_umaryland_0373D_10855.pdf
    Size:
    24.80Mb
    Format:
    PDF
    Download
    Author
    Sturgeon, Craig
    Advisor
    Fasano, Alessio
    Shea-Donohue, Terez
    Date
    2017
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    Increased small intestinal permeability has recently been described as an integral element, along with genetic makeup and environmental triggers, in the pathogenesis of chronic inflammatory diseases (CIDs). We identified zonulin as a master regular of intercellular tight junctions, and both our group and others have linked the zonulin pathway to the development of several CIDs. We further characterized zonulin as the precursor of haptoglobin (Hp)-2. In this dissertation, my aim is to study the role of zonulin-mediated small intestinal permeability in the pathogenesis of CIDs by using a zonulin transgenic mouse model as well as zonulin genotyping and disease modeling in several CIDs. Zonulin transgenic Hp2 mice (Ztm) were subjected to dextran-sodium-sulfate (DSS) treatment, and their morbidity and mortality compared to C57Bl/6 (WT) mice. We observed increased morbidity (more severe body weight loss and colonic inflammation) and mortality at 11 days post DSS treatment in zonulin transgenic Hp2 mice compared to WT. Ztm had increased small intestinal permeability at baseline compared to WT, which was exacerbated by DSS treatment and associated with upregulation of the zonulin gene in the small intestine. Treatment with the zonulin inhibitor AT1001 prevented the DSS-induced increased small intestinal permeability and completely reversed mortality rates. We went on to study the risk Hp genotypes in disease development by using a combination of HLA and Hp genotypes to predict disease outcome. We observed increased HP2 allele frequency in several CIDs studied. Additionally, the HP2 allele (both in homozygosity and heterozygosity) seems to increase the risk of early age of onset of Type 1 diabetes (T1D). Using the combination of HLA and Hp genotypes, we were able to create accurate positive predictive models for celiac disease (CD) and T1D. Taken together, these data show that the zonulin gene can be mechanistically linked to increased small intestinal permeability that leads to a break of tolerance with subsequent development of CIDs. Additionally, the use of the Hp genotype, either alone or in addition to other genetic markers, may be a useful tool to create predictive models for disease development for precision and preventive medicine approaches.
    Description
    University of Maryland, Baltimore. Molecular Medicine. Ph.D. 2017
    Keyword
    barrier function
    intestinal permeability
    zonulin
    Autoimmunity
    Inflammation
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/6732
    Collections
    Theses and Dissertations School of Medicine
    Theses and Dissertations All Schools

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  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.