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The role of tryptophan-rich basic protein (WRB) in inner hair cell synaptic transmission and hearingPanou, Iliana 08 May 2013 (has links)
No description available.
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Mathematical modelling and electrophysiological monitoring of the regulation of cochlear amplificationO'Beirne, Greg A. January 2005 (has links)
[Truncated abstract] The cochlea presumably possesses a number of regulatory mechanisms to maintain cochlear sensitivity in the face of disturbances to its function. Evidence for such mechanisms can be found in the time-course of the recovery of CAP thresholds during experimental manipulations, and in observations of slow oscillations in cochlear micromechanics following exposure to low-frequency tones (the “bounce phenomenon”) and other perturbations. To increase our understanding of these oscillatory processes within the cochlea, and OHCs in particular, investigations into cochlear regulation were carried out using a combination of mathematical modelling of the ionic and mechanical interactions likely to exist within the OHCs, and electrophysiological experiments conducted in guinea pigs. The electrophysiological experiments consisted of electrocochleographic recordings and, in some cases, measurement of otoacoustic emissions, during a variety of experimental perturbations, including the application of force to the cochlear wall, exposure to very-low-frequency tones, injection of direct current into scala tympani, and intracochlear perfusions of artificial perilymph containing altered concentrations of potassium, sodium, and sucrose. To obtain a panoramic view of cochlear regulation under these conditions, software was written to enable the interleaved and near-simultaneous measurement of multiple indicators of cochlear function, including the compound action potential (CAP) threshold, amplitude and waveshape at multiple frequencies, the OHC transfer curves derived from low-frequency cochlear microphonic (CM) waveforms, distortion-product otoacoustic emissions (DPOAEs), the spectrum of the round-window neural noise (SNN), and the endocochlear potential (EP). ... The mathematical model we have developed provided a physiologically-plausible and internally-consistent explanation for the time-courses of the cochlear changes observed during a number of different perturbations. We show that much of the oscillatory behaviour within the cochlea is consistent with underlying oscillations in cytosolic calcium concentration. We conclude that a number of the discrepancies between the simulation results and the experimental data can be resolved if the cytosolic calcium functions as two distinct pools: one which controls basolateral permeability and one which controls slow motility. This two-calcium-pool model is discussed.
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Expression analysis of the regenerating utricle sensory epithelia : from microarrays to parsing pathwaysHawkins, Raymond David. January 2005 (has links) (PDF)
Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Vita. Bibliography: 197-219.
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Stereocilia of sensory cells in normal and hearing impaired ears a morphological, physiological and behavioural study /Engström, Berit. January 1983 (has links)
Thesis (Doctoral)--Uppsala University, 1983. / Includes bibliographical references (p. 33-34).
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Perfil audiológico de adultos com e sem hipertensão arterial / Audiological profile of adults with and without arterial hypertensionMariana Aparecida Soares 16 May 2014 (has links)
Introdução: Sabe-se que muitas pessoas sofrem de hipertensão arterial sistêmica (HAS) e indivíduos cada vez mais jovens estão apresentando este quadro. A HAS pode causar várias complicações na saúde geral do indivíduo, em virtude do comprometimento da circulação sanguínea, o que pode afetar até mesmo o sistema auditivo. Porém, os estudos encontrados na literatura, até o momento, são bastante controversos quanto à influência ou não da HAS no sistema auditivo periférico. Objetivos: Verificar se existe influência da hipertensão arterial no sistema auditivo periférico, por meio dos achados na audiometria de altas frequências, nas emissões otoacústicas transientes e produto de distorção, comparando grupos de indivíduos normoouvintes pela audiometria convencional, com e sem HAS; e identificar se alguma das variáveis referentes às avaliações realizadas pode ser utilizada para discriminar os indivíduos nos grupos com ou sem HAS. Método: Participaram deste estudo 40 sujeitos de 30 a 50 anos, divididos em grupos com e sem hipertensão arterial. Todos os indivíduos foram submetidos à meatoscopia, imitanciometria, audiometria tonal nas frequências de 250 Hz a 16000 Hz, logoaudiometria, emissões otoacústicas evocadas transientes e emissões otoacústicas produto de distorção. Resultados: Não foi observada diferença estatisticamente significante entre os grupos com e sem HAS na audiometria convencional e em altas frequências. Para as emissões otoacústicas evocados por estímulo transiente, houve tendência à diferença estatisticamente significante, com as respostas do grupo com HAS piores que do grupo sem HAS. Já as emissões otoacústicas produto de distorção, nas frequências de 1501, 2002 e 3003 Hz, apresentaram diferenças estatisticamente significantes, sendo que o grupo com HAS apresentou amplitudes menores. A análise discriminante mostrou que as variáveis das emissões otoacústicas produto de distorção foram as que melhor discriminaram os indivíduos com e sem HAS. Conclusão: Nossos achados sugerem presença de disfunção coclear em indivíduos com hipertensão arterial, uma vez que as respostas das emissões otoacústicas foram piores no grupo com HAS / Introduction: It is widely known that many people have systemic arterial hypertension (SAH) and, currently, the number of young people with such disease is increasing. SAH may cause a wide range of complications in the general health of an individual due to the involvement of blood circulation, which may affect the hearing system. Nevertheless, the reports found in the scientific field are still controversial regarding the influence of SAH on the peripheral auditory system. Purpose: To verify if there is any influence of SAH on the peripheral auditory system, through data from high frequency audiometry, transient-evoked otoacustic emissions and distortion-product otoacoustic emissions and compare such results to groups of typical hearing individuals, with and without SAH, who underwent the pure-tone audiometry test; and also investigate if any variable regarding the hearing assessment may be used to differentiate individuals with and without SAH. Methods: This study counted on 40 individuals aged between 30 and 50 years old, divided into groups with and without SAH. All individuals underwent the following procedures: otoscopy, imitanciometry, pure-tone audiometry in frequencies from 250Hz to 16000 Hz, logoaudiometry, transient-evoked otoacoustic emissions and distortion-product otoacoustic emissions. Results: There was found no significant statistically difference between the groups with and without SAH neither in pure-tone nor high-frequency audiometry. Regarding transient-evoked otoacustic emissions there was a tendency to a significant statistically difference once the SAH group showed lower results. Concerning distortion-product otoacustic emissions there was found significant statistically difference in the following frequencies: 1501, 2002 e 2003 Hz in which the SAH group showed lower results. Discriminant analysis pointed that variables of distortion-product otoacustic emissions best distinguished individuals with and without SAH. Conclusion: Data from this study suggest cochlear dysfunction in individuals with SAH since their results in otoacoustic emissions were lower than in the group with SAH
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O papel da sinalização Notch na diferenciação do epitélio pulmonar. / The role of Notch signaling in lung epithelial differentiation.Michelle Vasconcelos 16 January 2012 (has links)
O epitélio pulmonar é formado por uma grande diversidade celular, que incluí: células secretoras, ciliadas, basais e neuroendócrinas (NE). A distribuição balanceada destes tipos celulares é crucial para a função pulmonar e pode ser dramaticamente alterada em doenças como a asma. Neste trabalho, estudamos o papel de Notch no pulmão em desenvolvimento ao inativar condicionalmente Rbpjk ou Pofut1, componentes críticos da sinalização Notch. Pulmões mutantes apresentaram-se superpopulados por células ciliadas e NE, além da ausência de células de Clara. Nossos dados sugeriram que Notch suprime os programas de diferenciação de células ciliadas e NE para permitir a diferenciação de células de Clara, através de um mecanismo de inibição lateral. Identificamos também genes associados com a diferenciação de células secretoras e ciliadas através de microarrays. A heterogeneidade no padrão de expressão gênica sugeriu que a via de sinalização Notch estabelece múltiplos subtipos de células ciliadas e secretoras no epitélio pulmonar em desenvolvimento. / The airway epithelium comprises a diverse population of secretory, ciliated, basal and neuroendocrine cells (NE). The proper balance of these cell types is critical for normal lung function and can be altered dramatically in conditions, such as asthma. We studied the role of Notch in airway progenitor cell fate by conditionally inactivating Rbpjk or Pofut1, two critical Notch pathway components in mouse mutants. This resulted in airways overpopulated with ciliated and NE cells and absence of secretory Clara cells. We found that Notch suppresses the ciliated and the NE cell programs to allow secretory cell differentiation through a lateral inhibition mechanism. We also identified genes associated with the differentiation of secretory and ciliated cells through a microarray gene profiling experiment. The great heterogeneity of gene expression patterns suggested that Notch plays a role in establishing multiple subsets of secretory and ciliated cells in the developing lung.
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Génération de progéniteurs otiques dérivés de cellules souches pluripotentes induites humaines (hiPSC) : application à la thérapie cellulaire dans l'oreille interne / Generation of otic progenitors from human induced pluripotent stem cells : cell-based therapy for inner earLahlou, Hanae 09 October 2017 (has links)
La surdité neurosensorielle est définie par une atteinte de l’oreille interne, il résulte principalement d’une perte de cellules ciliées (CC). Chez les mammifères, ce processus est malheureusement irréversible. Le développement de la thérapie cellulaire a fait naître de nouveaux espoirs pour le traitement des surdités neurosensorielles. Les cellules souches d’origine embryonnaire ou adulte seraient capables de se différencier in vitro en progéniteurs otiques et de restaurer partiellement les fonctions auditives in vivo après transplantation. Cependant, les protocoles de différenciation in vitro des CC à partir de cellules souches sont insatisfaisants, et les signaux qui contrôlent ce phénomène restent mal connus. Ainsi, l’objectif de ce travail de thèse était d’étudier in vitro la différenciation des CC à partir de cellules souches pluripotentes induites humaines (hiPSC). Nous nous sommes intéressés à deux voies de signalisation majeures impliquées dans le développement de l’oreille interne in vivo, la voie Notch et la voie Wnt. Dans une première partie, nous avons montré que l’inhibition tardive de la voie Notch favorise la différenciation des hiPSC en CC. Dans une seconde partie, nous avons étudié le rôle de la voie Wnt dans la différenciation des hiPSC en cellules otiques. Nos résultats indiquent que l'inhibition de la voie Wnt durant la première phase d’induction favorise l'expression des marqueurs de la placode otique et initie la spécification des CC.Les travaux présentés dans cette thèse améliorent ainsi les protocoles de différenciation des hiPSC et suggèrent que ce type de cellules serait parfaitement adapté pour traiter les surdités neurosensorielles. / Neurosensory hearing loss is associated to inner ear disorders and degeneration of hair cells (HCs). Unfortunately, this process is irreversible in mammals. Currently, no curative treatment allows these cells to regenerate. For this reason, the development of cell therapy arose new hopes for the treatment of neurosensory hearing loss. Stem cells, either of embryonic or adult origin, seem able to differentiate in vitro into otic progenitors and to partially restore auditory functions in vivo. However, current protocols for in vitro differentiation of stem cells into HCs are unsatisfactory, and the signals that control this phenomenon remain poorly understood. Thus, the objective of this thesis was to study in vitro HC differentiation from human induced pluripotent stem cells (hiPSCs). We were particularly interested in two major signaling pathways involved in vivo in inner ear development, the Notch and Wnt signaling pathways.In a first part, we demonstrated that Notch inhibition during late otic differentiation enhances hiPSC differentiation into hair cell-like cells. In a second part, we studied the role of the Wnt signaling pathway during otic induction and HC specification. Our results indicate that Wnt inhibition during early otic induction promotes the expression of otic placode markers and initiate HC specification. The work presented here thus propose improved protocols to obtain HCs from hiPSCs, and suggest that this cell type is perfectly adapted for the treatment of neurosensory hearing loss.
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Biologie des cellules souches cochléaires : perspectives dans le traitement de la surdité sensorielle / Stem cell biology of the inner ear : potential therapeutic application of sensory deafnessSavary, Etienne 14 December 2010 (has links)
La destruction des cellules ciliées de la cochlée entraine des surdités sensorielles. Chez les mammifères ces cellules ne se régénèrent pas et les déficits auditifs occasionnés sont définitifs. Aucune thérapie visant à remplacer les cellules ciliées détruites n'est actuellement proposée.L'objectif de cette thèse est de contribuer au développement d'une thérapie cellulaire basée sur la greffe de cellules souches / progénitrices cochléaires et destinée à promouvoir la régénération des cellules ciliées.Au cours de nos travaux, nous avons isolé une population de cellules souches cochléaires chez des souris néonatales appartenant à la « side population » (Savary et al. 2007). Nous avons également montré, par des expériences de perte et de gain de fonction in vitro, que la voie de signalisation Notch est nécessaire pour l'auto-renouvellement et la différenciation de ces cellules (Savary et al., 2008). Des lignées de souris transgéniques exprimant la GFP sous le promoteur de la GFAP et de la Nestine nous ont permis de suivre l'expression de ces marqueurs de cellules souches dans des cochlées de souris P3 et adultes. En étudiant l'expression combinée d'autres marqueurs comme Sox2 et Abcg2, nous avons montré que les cellules progénitrices cochléaires sont réparties différemment chez les souris néonatales et les souris adultes (Smeti, Savary et al 2010).Nos expériences préliminaires de transplantation in vitro dans un modèle murin de surdité génétique humaine de type DFNA15 démontrent que les cellules souches / progénitrices greffées sont capables d'intégrer l'épithélium sensoriel lésé et de se différencier en cellules exprimant un marqueur de cellules ciliées. / The destruction of cochlear hair cells causes sensory deafness. In Mammals these cells do not regenerate and damages are irreversible. Currently, there is no proposed therapy to replace the destroyed hair cells.The focus of this thesis is to develop a novel cell therapy based on transplantation of cochlear progenitor cells in order to promote regeneration of hair cells.We first isolated a population of cochlear stem cells from neonatal mice by using the side population analysis technique (Savary et al. 2007). Then, we showed, by in vitro loss and gain of function experiments, that the Notch signaling pathway is necessary for cellular self-renewal and differentiation (Savary et al., 2008).Transgenic mice strains expressing GFP under the control of GFAP and Nestin promotors allowed us to monitor the expression of these markers of stem cells in the P3 and adult mice cochleae. By studying the combined expression of other stem cells markers such as Sox2 and ABCG2, we showed that the niches of cochlear progenitor cells are differently distributed in neonatal and adult mice (Smati, Savary et al 2010).Our preliminary in vitro transplantation experiments in a mouse model that mimics human genetic deafness DFNA15 show that the transplanted stem / progenitor cells are able to migrate to the lesion site, to integrate the damaged sensory epithelium and to differentiate into cells expressing a marker of hair cells.
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The effect of Nystatin on the inner ear : an experimental guinea pig studyWoods, Owen 08 1900 (has links)
Objectifs:
Le Nystatin est un antibiotique efficace pour le traitement d’otomycose. Bien que sa
sécurité au niveau de l’oreille externe soit bien établie, son utilisation n’est pas
recommandée lorsqu’il y a une perforation tympanique. L’objectif de cette étude est
d’évaluer le potentiel ototoxique du Nystatin lorsque celui-ci est appliqué directement au
niveau de l’oreille moyenne.
Méthodes:
Nous avons fait une étude expérimentale avec 18 cochons d’Indes de souche Hartley que
nous avons divisés en deux groupes. En exposant l’oreille moyenne de chaque animal au
Nystatin (groupe I) ou à la néomycine (groupe II) et chaque oreille controlatérale à une
solution physiologique (NaCl), la fonction auditive a été évaluée avec un test de
potentiels évoqués auditif du tronc cérébral avant et après les injections. Une étude par
microscopie électronique a permis une comparaison histologique de l’état des cellules
ciliées cochléaires entre les 2 groupes.
Résultats:
Les pertes auditives moyennes du groupe « Nystatin » étaient de 13.0 dB et comparables
aux pertes moyennes observées dans les oreilles ayant été injectées avec du NaCl (4.0 dB
dans le groupe I et 15.1 dB dans le groupe II). Le groupe de contrôle « néomycine » a
subi une perte auditive moyenne de 39.3 dB, ce qui représente une différence
cliniquement et statistiquement significative (p<0.001). L’étude histologique avec une
microscopie à balayage électronique a démontré une conservation de l’architecture des
cellules ciliées cochléaires dans les groupe Nystatin et NaCl. La néomycine a causé une
destruction marquée de ces structures.
Conclusions:
Le Nystatin ne provoque pas d’atteinte auditive ni de destruction des cellules ciliées
externes après injection directe dans l’oreille moyenne chez le cochon d’Inde. / Objective:
Nystatin is an effective topical antifungal agent widely used in the treatment of
otomycosis. Though it is safe for external ear use, current recommendations are to avoid
its use in cases of tympanic membrane perforation. The objective of our study was to test
the security of Nystatin when applied directly to the middle ear of a guinea pig model.
Methods:
We performed an experimental study with 18 Hartley guinea pigs that were divided into
two groups. Exposing middle ears from one group to Nystatin (group I) and from the
other to the ototoxic neomycin (group II), we compared results of auditory brainstem
response (ABR) testing at three intervals during the study. Each animal’s contralateral
ear was injected with a physiological solution (NaCl). At the end of the study, we
performed a histological analysis of the animals’ cochleae using a scanning electron
microscope.
Results:
Average hearing loss in the Nystatin group was 13.0 dB which was similar to the results
obtained in the NaCl-exposed ears (4.0 dB in group I and 15.1 dB in group II). Average
hearing loss in the neomycin group was 39.3 dB, which represents a clinically significant
difference (p<0.001). Scanning electron microscope evaluation revealed intact cochlear
hair cell architecture in the Nystatin and normal saline groups, compared to important
destruction in the neomycin group.
Conclusion:
Nystatin does not cause hearing impairment or cochlear hair cell damage when exposed
directly to the middle ear of a guinea pig model.
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Exploration du rôle des différents domaines C2 de l'otoferline et des isoformes des canaux calciques CaV1.3 dans la transmission synaptique des cellules ciliées auditives / Exploring the role of the various C2 domains of otoferlin and isoforms of calcium channels CaV1.3 in synaptic transmission of auditory hair cellsTertrais, Margot 19 December 2018 (has links)
L'encodage du signal acoustique en impulsions nerveuses se réalise au niveau des synapses à ruban des cellules ciliées internes (CCI) de la cochlée. Une dépolarisation déclenche l'exocytose des vésicules synaptiques suite à l'activation des canaux calciques CaV1.3 et à l'action d'un senseur calcique particulier, l'otoferline, une grande protéine se composant d'un domaine transmembranaire en C-terminal et de six domaines C2 (A-F) pouvant lier le Ca2+ et les phospholipides. Afin de caractériser le rôle de ces différents domaines C2, nous avons utilisé des vecteurs viraux (AAV) permettant l'expression de formes raccourcies de l'otoferline (mini-Otof) in vivo dans les CCI de souris dépourvues d'otoferline (Otof -/-). Nous montrons que les mini-Otof contenant les domaines C2-EF, C2-DEF ou C2-ACEF sont suffisantes pour restaurer l'exocytose rapide des CCI Otof -/-, sans toutefois restaurer l'audition car le recrutement des vésicules synaptiques reste altéré. Nous révélons pour la première fois la présence d'une endocytose ultra-rapide (t < 20 ms) dynamine- et otoferline-dépendante, une fonction certainement essentielle à l'homéostasie membranaire des CCI. L'expression des mini-Otof C2-EF et C2-DEF a également permis de restaurer partiellement la composante rapide de l'inactivation du courant calcique des CCI, celle-ci étant absente chez les souris Otof -/-. Cette inactivation rapide est réalisée par les isoformes courtes Cav1.3S qui ont leur partie C-terminale régulatrice tronquée, contrairement aux isoformes longues Cav1.3L dépourvues d'inactivation. Afin de différencier les rôles spécifiques de ces isoformes dans le cycle des vésicules synaptiques, nous avons utilisé la technologie CRISPR-Cas9, nous permettant d'éditer spécifiquement la partie C-terminale régulatrice des canaux Cav1.3L. Nos résultats montrent que les souris CRISPR-Cav1.3L présentent une surdité sévère expliquée au niveau des CCI par un défaut de recrutement vésiculaire aux zones actives, alors que les Cav1.3S inaltérés contrôlent la fusion rapide des vésicules synaptiques. / The precise encoding of acoustic signals into nerve impulses is achieved at the ribbon synapses of inner hair cells (IHC) of the cochlea. Exocytosis of synaptic vesicles by IHC is triggered by voltage-activation of Cav1.3 calcium channels and the action of a specific calcium sensor, otoferlin, a large protein with a single C-terminal transmembrane domain and six C2 (A-F) domains which binds Ca2+ and interacts with phospholipids. In order to characterize the function of the various otoferlin C2 domains, we used viral vectors (AAV) allowing the expression of shortened forms of otoferlin (mini-Otof), in vivo, in IHC from mice lacking otoferlin (Otof -/-). We show that mini-Otof containing C2-EF, C2-DEF or C2-ACEF domains are sufficient to restore fast synaptic vesicle exocytosis in Otof -/- IHC, but without restoring hearing because vesicular replenishment remains impaired. For the first time, we also uncover an ultra-fast endocytosis (t < 20 ms) dynamin- and otoferlin-dependant, a function that is certainly essential for a fast regulation of IHC membrane homeostasis. Furthermore, the expression of the mini-Otof C2-EF and C2-DEF also partially restored the fast component of the Ca2+ current inactivation in Otof -/- IHC. This rapid inactivation is carried out by Cav1.3S short isoforms which have a truncated C-terminal regulatory domain, unlike Cav1.3L long isoforms which display no inactivation. To characterize the specific role of these Cav1.3 isoforms, we used CRISPR-Cas9 technology, allowing a specific removal of the C-terminal regulatory part of the Cav1.3L channels in IHC. Our results show that CRSIPR- Cav1.3L mice display severe deafness explained at the IHC level by a defect in vesicular replenishment of the active zones, while Cav1.3S are sufficient to ensure fast and transient exocytosis of docked synaptic vesicles.
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