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dc.contributorDepartment of Biomedical Engineeringen_US
dc.contributor.advisorSun, Lei (BME)en_US
dc.creatorZhu, Ting-
dc.identifier.urihttps://theses.lib.polyu.edu.hk/handle/200/13149-
dc.languageEnglishen_US
dc.publisherHong Kong Polytechnic Universityen_US
dc.rightsAll rights reserveden_US
dc.titleManipulations of mechanosensitive ion channels in neuronal activities and microglial functionsen_US
dcterms.abstractMechanosensitive ion channels, located on the cell membrane, convert mechanical signals into electrical and chemical signals, and then alter the functions of cells when cells are stimulated by mechanical cues. Thus, it is feasible to alter the activity of cells by modifying the activity of mechanosensitive ion channels. In this thesis, we explored to manipulate mechanosensitive ion channel CFTR to inhibit neuronal activities by physical intervention method-ultrasound. We also explored the function of the mechanosensitive ion channel Piezo1 in microglia and regulate it using pharmacological approaches.en_US
dcterms.abstractUltrasound neuromodulation has recently received much attention owing to its non-invasiveness to give potential for clinical translation. Sonogenetics renders neurons sensitive to ultrasound stimuli without affecting naïve cells. Mediators to activate neuron activity by ultrasound are studied well while little mediators have been discovered to inhibit neuron activity. Here, we found a mechanosensitive chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) could be probed by ultrasound and then achieve neuronal inhibition effect both in vitro and in vivo. We found ultrasound could induce chloride influx and hyperpolarization of primary neuron overexpressing CFTR and this strategy could inhibit neuron excitation by NMDA in vitro. We tested the inhibitory effect of our strategy using an epilepsy model induced by intraperitoneal injection of kainic acid, and we discovered that CFTR may also mediate the ultrasonic inhibitory effect, thereby reducing the seizures in vivo. Taken together, we found a new mediator to facilitate ultrasound neuronal inhibitory effect and suggests a viable therapeutic approach for disorders of the brain characterized by neuronal hyperexcitation, such as epilepsy.en_US
dcterms.abstractMicroglia are the brain’s resident immune cells, performing surveillance to promote homeostasis and healthy functioning. While microglial chemical signaling is well-studied, mechanical cues regulating their function are less well-understood. Here, we investigate the role of the mechanosensitive ion channel Piezo1 in microglia migration, pro-inflammatory cytokine production and stiffness sensing. In Piezo1 knockout transgenic mice, we demonstrated the functional expression of Piezo1 in microglia and identified genes whose expression was consequently affected. Functional assays revealed that Piezo1-deficiency in microglia enhanced migration towards amyloid β-protein, and decreased levels of pro-inflammatory cytokines produced upon stimulation by lipopolysaccharide, both in vitro and in vivo. The phenomenon could be mimicked or reversed chemically using a Piezo1-specific agonist or antagonist. Finally, we also showed that Piezo1 mediated the effect of substrate stiffness-induced migration and cytokine expression. Altogether, we show that Piezo1 is an important molecular mediator for microglia, its activation modulating microglial migration and immune responses.en_US
dcterms.extent125 pages : color illustrationsen_US
dcterms.isPartOfPolyU Electronic Thesesen_US
dcterms.issued2023en_US
dcterms.educationalLevelPh.D.en_US
dcterms.educationalLevelAll Doctorateen_US
dcterms.LCSHIon channelsen_US
dcterms.LCSHMembrane proteinsen_US
dcterms.LCSHUltrasonics in medicineen_US
dcterms.LCSHMicrogliaen_US
dcterms.LCSHHong Kong Polytechnic University -- Dissertationsen_US
dcterms.accessRightsopen accessen_US

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Please use this identifier to cite or link to this item: https://theses.lib.polyu.edu.hk/handle/200/13149