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

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dc.contributor.advisorTerman, Jonathan R.en
dc.contributor.committeeMemberHerz, Joachimen
dc.contributor.committeeMemberYu, Gangen
dc.contributor.committeeMemberBezprozvanny, Ilyaen
dc.creatorCenik, Basar 1981-en
dc.date.accessioned2015-01-13T23:47:34Z
dc.date.available2015-01-13T23:47:34Z
dc.date.created2012-12
dc.date.issued2012-12-05
dc.date.submittedDecember 2012
dc.date.updated2015-01-13T23:47:03Z
dc.description.abstractFrontotemporal 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.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc900282009
dc.identifier.urihttps://hdl.handle.net/2152.5/ETD-UTSWMED-2012-12-61
dc.identifier.urihttps://hdl.handle.net/2152.5/1472
dc.language.isoenen
dc.subjectExcitatory Amino Acid Transporter 1en
dc.subjectFrontotemporal Dementiaen
dc.subjectHistone Deacetylase Inhibitorsen
dc.subjectIntercellular Signaling Peptides and Proteinsen
dc.titleProgranulin Biology: Small Molecule Enhancers of Progranulin Expression and Biochemical Analysis of Granulin Receptorsen
dc.typeThesisen
dc.type.materialTexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineNeuroscienceen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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