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    Progranulin Biology: Small Molecule Enhancers of Progranulin Expression and Biochemical Analysis of Granulin Receptors

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    Basar Cenik Dissertation Dec 2012 No vitae.pdf (1.774Mb)
    Date
    2012-12-05
    Author
    Cenik, Basar 1981-
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    Abstract
    Frontotemporal dementia (FTD) is the second most common presenile dementia syndrome. Mutations in the GRN gene account for about 20% of patients with familial FTD. The protein encoded by GRN, progranulin, is a secreted glycoprotein with growth factor-like and immunomodulatory activities. Human progranulin contains seven granulin domains (denoted granulins A through F) that can be individually liberated following proteolytic cleavage. It is uncertain whether the holoprotein, the granulins or both mediate the biological effects of progranulin. All pathogenic GRN mutations result in haploinsufficiency and decreased extracellular progranulin. Therefore, increasing progranulin expression from the wild-type allele or (pro)granulin receptor agonists may be therapeutic in FTD. The overall goals of the work presented here were to identify small molecule enhancers of progranulin expression and (pro)granulin receptors that can be drug targets for the treatment and prevention of GRN deficient FTD. As described here, I discovered that suberoylanilide hydroxamic acid (SAHA), an FDA-approved histone deacetylase (HDAC) inhibitor, enhances GRN expression and nearly normalizes progranulin levels in haploinsufficient primary human cells from GRN mutation carriers. I also discovered that granulin A binds three proteins in solubilized extracts of rodent brain membranes: wolframin, excitatory amino acid transporter 1 (EAAT1), and the α3 subunit of the Na+/K+ ATPase. I argue that these proteins are candidates for a putative granulin receptor.
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    http://hdl.handle.net/2152.5/ETD-UTSWMED-2012-12-61
    http://hdl.handle.net/2152.5/1472
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    UT Southwestern Health Sciences Digital Library and Learning Center | 5323 Harry Hines Boulevard, Dallas, Texas 75390-9049
    Telephone 214-648-2001 | Email
    Library Home | UT Southwestern Home
    DSpace software copyright © 2002-2016  DuraSpace
    Contact Us | Send Feedback
    TDL
    Theme by 
    Atmire NV