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dc.contributor.advisorParker, Kevin Kit
dc.contributor.authorDabiri, Borna Esfahani
dc.date.accessioned2014-06-06T23:28:03Z
dash.embargo.terms2016-06-04en_US
dash.embargo.terms2016-06-04
dc.date.issued2014-06-06
dc.date.submitted2014
dc.identifier.citationDabiri, Borna Esfahani. 2014. Inter- and Intracellular Effects of Traumatic Axonal Injury. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard:11339en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12274601
dc.description.abstractMild Traumatic Brain Injuries (mTBIs) are non-penetrating brain injuries that do not result in gross pathological lesions, yet they may cause a spectrum of cognitive and behavioral deficits. mTBI has been placed in the spotlight because of increased awareness of blast induced and sports-related concussions, but the underlying pathophysiological mechanisms are poorly understood. Several studies have implicated neuronal membrane poration and ion channel dysfunction as the primary mechanism of injury. We hypothesized that injury forces utilize mechanically-sensitive, transmembrane integrin proteins, which are coupled to the neuronal cytoskeleton (CSK) and distribute injury forces within the intracellular space, disrupting CSK organization and reducing intercellular neuronal functionality. To test this, magnetic beads were coated with adhesive protein, allowing them to bind to integrins in the neuronal membrane in vitro. To apply forces to the neurons via the bound beads, we built custom magnetic tweezers and demonstrated that focal adhesions (FACs) formed at the site of bead binding. We showed that the beads were coupled to the CSK via integrins by measuring the disparate adhesion of the soma and neurite to their underlying substrate. The soma also required more force to detach than neurites, correlating with the FAC density between each neuronal microcompartment and substrate. We then utilized the magnetic tweezers to test whether beads bound to integrins injured neurons more than beads that bound to neurons nonspecifically. Integrin-bound beads injured neurons more often and the injury was characterized by the formation of focal swellings along axons, reminiscent of Diffuse Axonal Injury. While integrin-bound beads initiated swellings throughout neurons, beads bound nonspecifically only caused local injury where beads were attached to neurons. To demonstrate the electrical dysfunction of integrin-mediated injury forces, we adapted Magnetic Twisting Cytometry to simultaneously apply injury forces to beads bound to multiple cells within neuronal networks in vitro. The formation of focal swellings resulted in reduced axonal electrical activity and decreased coordinated network activity. These data demonstrate that the mechanical insult associated with mTBI is propagated into neurons via integrins, initiating maladaptive CSK remodeling that is linked to impaired electrical function, providing novel insight into the underlying mechanisms of mTBI.en_US
dc.description.sponsorshipEngineering and Applied Sciencesen_US
dc.language.isoen_USen_US
dash.licenseLAA
dc.subjectBiomedical engineeringen_US
dc.subjectCytoskeletonen_US
dc.subjectIntegrinen_US
dc.subjectMagnetic Tweezersen_US
dc.subjectMagnetic Twisting Cytometryen_US
dc.subjectTraumatic Axonal Injuryen_US
dc.subjectTraumatic Brain Injuryen_US
dc.titleInter- and Intracellular Effects of Traumatic Axonal Injuryen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorDabiri, Borna Esfahani
dc.date.available2016-06-04T07:30:56Z
thesis.degree.date2014en_US
thesis.degree.disciplineEngineering and Applied Sciencesen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberWeitz, Daviden_US
dc.contributor.committeeMemberSmith, Mauriceen_US
dc.contributor.committeeMemberZafonte, Rossen_US
dash.contributor.affiliatedDabiri, Borna


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