TAAR1-dependent astrocyte dysregulation during HAND and METH exposure

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dc.contributor.advisorGhorpade, Anuja
dc.contributor.committeeMemberBasu, Alakananda
dc.contributor.committeeMemberBarber, Robert C.
dc.contributor.committeeMemberGatch, Michael B.
dc.contributor.committeeMemberKrishnamoorthy, Raghu R.
dc.creatorMythen, Shannon
dc.date.accessioned2019-08-22T19:41:03Z
dc.date.available2019-08-22T19:41:03Z
dc.date.issued2018-12
dc.date.submitted2018-12-13T14:12:12-08:00
dc.description.abstractExcitatory amino-acid transporter (EAAT)-2 is predominantly expressed in astrocytes and clears glutamate from tripartite synapses preventing excitotoxicity. EAAT- 2 dysregulation occurs during human immunodeficiency virus (HIV)-associated neuroinflammation and methamphetamine (METH) abuse, leading to neurotoxic outcomes. Trace amine associated receptor (TAAR) 1, a METH receptor in astrocytes, triggers EAAT-2 dysfunction. Protein kinase C (PKC) signaling promotes ubiquitination of EAAT-2 C-terminal lysine residues, resulting in EAAT-2 internalization. As a G protein coupled receptor, TAAR1's signaling is implicated in PKC activation. In this work, we investigated the role of TAAR1 in PKC-mediated EAAT-2 ubiquitination during HIV- associated neurocognitive disorders (HAND) and METH comorbidities. We evaluated a TAAR1 overexpression model in primary astrocytes to elucidate TAAR1-mediated functional changes. We found that TAAR1-selective inhibitor, EPPTB, reduced EAAT-2 ubiquitination, and a PKC activator decreased glutamate clearance in METH-pretreated human astrocytes. Therapies targeting astrocyte dysfunction may improve outcomes during HAND, METH abuse and other neuroinflammatory disorders.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/26702
dc.language.isoen
dc.provenance.legacyDownloads0
dc.subjectEAAT-2
dc.subjectglutamate clearance
dc.subjectHIV
dc.subjectinflammation
dc.subjectPKC
dc.subjectubiquitination
dc.subject.meshGlutamate Plasma Membrane Transport Proteins/metabolism
dc.subject.meshExcitatory Amino Acid Transporter 2/metabolism
dc.subject.meshAstrocytes
dc.subject.meshHIV-1
dc.subject.meshUbiquitination
dc.titleTAAR1-dependent astrocyte dysregulation during HAND and METH exposure
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineMicrobiology and Immunology
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameMaster of Science

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