Dissertations / Theses on the topic 'Stereocilin'
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Iranfar, Sepideh. "AAV-mediated gene therapy restores hearing and central auditory processing in a mouse model of human DFNB16 Deafness." Electronic Thesis or Diss., Sorbonne université, 2024. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2024SORUS127.pdf.
Full textHearing impairment stands as a significant contributor to disability, affecting over half a billion individuals throughout their lifespans. Despite its pervasive prevalence, no curative treatment currently exists. My Ph.D. project is translational, aiming to establish the proof of concept that viral gene therapy can restore hearing in a preclinical model for DFNB16 deafness. DFNB16, considered the second most common cause of hearing impairment, is caused by mutations in the stereocilin (STRC) gene and is characterized by mild-to-moderate deafness. The stereocilin (STRC) protein is predominantly expressed in outer hair cells (OHCs), one of the two types of cochlear sensory hair cells, responsible for sound amplification. STRC protein is crucial for the cohesion and maintenance of OHC bundles. Mutations in STRC result in defective OHCs, leading to abolished cochlear amplification and subsequent reduction in hearing sensitivity. As of now, there exists no cure for DFNB16.My main objective was to develop an adeno-associated virus (AAV)-based gene therapy to replace the mutant gene with its correct copy in a DFNB16 mouse model. Given the large size of the Strc coding sequence, exceeding AAV packaging capacity, I employed a hybrid dual-vector strategy to load Strc cDNA into AAV capsids. Since OHCs are inherently difficult to transduce with AAV vectors, we firstly conducted a comparative analysis of AAV cellular tropism within the inner ear to identify the most efficient AAV serotype for targeting OHCs. Secondly, I used the best performing AAV serotype to construct the therapeutic vector, which was administered into the cochleas of DFNB16 mice.Following the gene therapy, we found a robust restoration of STRC protein expression and its appropriate targeting at the tips of OHC stereocilia in treated mice. This process results in the restoration of the normal morphostructure of OHC bundles and cochlear amplification, ensuring stable and long-lasting restoration of hearing in the treated mice, similar to those of the wild-type mice. Notably, psychometric measurements of frequency perception using a Go/NoGo task demonstrated that frequency discrimination exhibited by the treated Strc-/- mice was comparable to those of wild-type mice, underscoring the efficacy of gene therapy in recovering essential features of natural sound perception associated with DFNB16. This finding lays the foundation for effective translational gene therapy for DFNB16 patients and facilitates the development of preclinical gene therapy studies for mouse models of human deafness
Gomez, Salvador Gustavo. "Protein Phosphatase 1 Concentrates at the Base of Sensory Hair Cell Stereocilia, Where it May Function in Stereocilia Cytoskeletal Structure." Ohio University Art and Sciences Honors Theses / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ouashonors1556276688823712.
Full textKitajiri, Shinichiro. "Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia." Kyoto University, 2005. http://hdl.handle.net/2433/144706.
Full textPeng, Anthony Wei. "A hair bundle proteomics approach to discovering actin regulatory proteins in inner ear stereocilia." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/54588.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (p. 137-154).
Because there is little knowledge in the areas of stereocilia development, maintenance, and function in the hearing system, I decided to pursue a proteomics-based approach to discover proteins that play a role in stereocilia function. I employed a modified "twist-off" technique to isolate hair bundle proteins, and I developed a method to purify proteins and to process them for analysis using multi-dimensional protein identification technology (MudPIT). The MudPIT analysis yielded a substantial list of proteins. I verified the presence of 21 out of 34 (62%) existing proteins known to be present in stereocilia. This provided strong evidence that my proteomics approach was efficient in identifying hair bundle proteins. Next, I selected three proteins and localized them to murine cochlear stereocilia. StarD10, a putative phospholipid binding protein, was detectable along the shaft of stereocilia. Nebulin, a putative F-actin regulator, was located toward the base of stereocilia. Finally, twinfilin 2, a putative modulator of actin polymerization, was found at the tips of stereocilia. In order to determine the function of twinfilin 2, I localized the protein predominately to the tips of shorter stereocilia where it is up-regulated during the final phase of elongation. When overexpressed, I found that twinfilin 2 causes a shortening of microvilli in LLC-PK1/CL4 cells and in native cochlear stereocilia. The main result of this thesis was determining the sub-cellular localization of three interesting proteins and functionally characterizing one protein. My thesis also confirmed the proteomics screen I developed as an efficient method for identifying proteins in stereocilia.
by Anthony Wei Peng.
Ph.D.
Shih-Wei, Chou. "FASCIN 2B IS A COMPONENT OF ZEBRAFISH STEREOCILIA AND A REGULATOR OF THEIR DIMENSIONS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1422016622.
Full textHu, Jiaqi. "TARGETING MECHANOTRANSDUCTION-RELATED GENES OF THE HAIR CELLUSING TALEN AND CRISPR/CAS TECHNOLOGY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1417780489.
Full textHwang, Philsang. "An In Vivo Study of the Function and Dynamics of Stereociliary Proteins." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1418833642.
Full textKulkarni, Prateek. "Interaction of MYO6 and CLIC5: An Interdependent Relation in the Hair Bundle Maintenance." Ohio University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1533730672111802.
Full textWaddell, Benjamin B. "CLIC5 maintains lifelong structural integrity of sensory stereocilia by promoting Radixin phosphorylation in hair cells of the inner ear." Ohio University Honors Tutorial College / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ouhonors1461332124.
Full textHadi, Shadan. "MYOSIN-XVA IS KEY MOLECULE IN ESTABLISHING THE ARCHITECTURE OF MECHANOSENSORY STEREOCILIA BUNDLES OF THE INNER EAR HAIR CELLS." UKnowledge, 2018. https://uknowledge.uky.edu/medsci_etds/9.
Full textSyam, Diana. "Immobilizing Mutation in an Unconventional Myosin15a Affects not only the Structure of Mechanosensory Stereocilia in the Inner Ear Hair Cells but also their Ionic Conductances." UKnowledge, 2014. http://uknowledge.uky.edu/medsci_etds/2.
Full textRicaud, Bruno. "Système de reconstruction d'environnement pour une aide au pilotage en environnement naturel." Thesis, Paris Sciences et Lettres (ComUE), 2016. http://www.theses.fr/2016PSLEM018/document.
Full textArmored vehicule driving is difficult because of low visibility given to pilots in tough environnements conditions and complex situations they have to manage.Soldiers safety and vehicle integrity are part of main topics for French “Armée de Terre”. To answer the problem Make the driving of military vehicles safer by improving environnement perception through driver asssistance systems, we study driving assistance in unstructured environnemnt by looking for sensors and methods which are suitable to realize such a system.First, we study existing methods and algorithms which fit our application case. Conclusion of this study is the definition of our system.Second, thanks to the previous study we explain the creation of an experimentation platform allowing evaluation of our concept. Data obtained from reconstruction are then exploited through environment analysis to bring obstacle extraction methods.Third, study of an alternative display solution is exposed and complete this work in explaining impact of restitution in operating cycle
Xue, Jingbing. "Morphometry of Hair Cell Bundles and Otoconial Membranes in the Utricle of a Turtle, Trachemys scripta." Ohio : Ohio University, 2006. http://www.ohiolink.edu/etd/view.cgi?ohiou1155672444.
Full textJoshi, Yuvraj. "Mécanismes à l'origine de la surdité DFNA25." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT041.
Full textDFNA25 is an autosomal-dominant and progressive form of human deafness caused by mutations in the SLC17A8 gene, which encodes the vesicular glutamate transporter type 3 (VGLUT3). To resolve the mechanisms underlying DFNA25, we studied the phenotype of the mouse harboring the p.A211V mutation in human (corresponding to p.A224V in mouse). Using auditory brainstem response and distortion products of otoacoustic emissions, we showed that VGLUT3A224V/A224V mouse replicates DFNA25 progressive hearing loss with intact cochlear amplification. Scanning electron microscopy examinations demonstrated fused stereocilia bundle of the inner hair cells (IHCs) as the primary cause for DFNA25. In addition, we observed a change in the structure-function of the IHC ribbon synapse at later stages. Using super-resolution microscopy, we noticed an elongation of the synaptic ribbon, associated with an increase in the rate of the sustained releasable pool of exocytosis. These results indicate that the primary defect in DFNA25 stems from a defective mechano-transduction followed by a change in the synaptic transfer
Roy, Pallabi. "Stereocilia Morphogenesis and Maintenance is Dependent on the Dynamics of Actin Cytoskeletal Proteins." Thesis, 2019. http://hdl.handle.net/1805/18755.
Full textAge-related hearing loss is an acute health problem affecting people worldwide, often arising due to defects in the proper functioning of sensory hair cells in the inner ear. The apical surface of sensory hair cells contains actin-based protrusions known as stereocilia, which detect sound and head movements. Since hair cells are not regenerated in mammals, it is important to maintain the functioning of stereocilia for the life of an organism to maintain hearing ability. The actin filaments within a stereocilium are extensively crosslinked by various actin crosslinking proteins, which are important for stereocilia development and maintenance. Multiple studies have shown that the stereocilia actin core is exceptionally stable whereas actin is dynamic only at the tips of stereocilia. However, whether the actin crosslinking proteins, which are nearly as abundant as actin itself, are similarly stable or can freely move in and out of the core remains unknown. Loss or mutation of crosslinkers like plastin-1, fascin-2, and XIRP2 causes progressive hearing loss along with stereocilia degeneration while loss of espin prevents stereocilia from even developing properly. Do these phenotypes stem from an unstable stereocilia core? Does crosslinking confer stability to the core? To address these questions, we generated novel transgenic reporter lines to monitor the dynamics of actin in mice carrying fascin-2R109H mutation and espin null mice and also to study the dynamics of actin crosslinkers, in vivo and ex-vivo. We established that actin crosslinkers readily exchange within the highly stable F-actin structure of the stereocilia core. In addition, we determined that stereocilia degeneration in mice carrying fascin-2R109H mutation and espin null mice could possibly occur due to a less stable actin core. These studies suggest that dynamic crosslinks stabilize the core to maintain proper stereocilia functioning. Future work warrants understanding the reason behind the importance of dynamic crosslinks within a stable stereocilia core. Actin stability not only depends on actin crosslinkers, but also on actin filament composition as evident from distinct stereocilia degeneration and progressive hearing loss patterns in hair-cell specific knockout of actin isoforms. Although beta- and gamma- actin polypeptide sequences differ by only 14 four amino acids, whether the latter determine the unique function of each cytoplasmic actin isoform was previously unknown. Here we determined that these four critical amino acids determine the unique functional importance of beta-actin isoform in sensory hair cells. Taken together, our study demonstrates that actin cytoskeletal proteins are important for the morphogenesis and maintenance of stereocilia.
(6481925), Pallabi Roy. "Stereocilia Morphogenesis and Maintenance is dependent on the Dynamics of Actin Cytoskeletal Proteins." Thesis, 2019.
Find full textAge-related hearing loss is an acute health problem affecting people worldwide, often arising due to defects in the proper functioning of sensory hair cells in the inner ear. The apical surface of sensory hair cells contains actin-based protrusions known as stereocilia, which detect sound and head movements. Since hair cells are not regenerated in mammals, it is important to maintain the functioning of stereocilia for the life of an organism to maintain hearing ability. The actin filaments within a stereocilium are extensively crosslinked by various actin crosslinking proteins, which are important for stereocilia development and maintenance. Multiple studies have shown that the stereocilia actin core is exceptionally stable whereas actin is dynamic only at the tips of stereocilia. However, whether the actin crosslinking proteins, which are nearly as abundant as actin itself, are similarly stable or can freely move in and out of the core remains unknown. Loss or mutation of crosslinkers like plastin-1, fascin-2, and XIRP2 causes progressive hearing loss along with stereocilia degeneration while loss of espin prevents stereocilia from even developing properly. Do these phenotypes stem from an unstable stereocilia core? Does crosslinking confer stability to the core? To address these questions, we generated novel transgenic reporter lines to monitor the dynamics of actin in mice carrying fascin-2R109H mutation and espin null mice and also to study the dynamics of actin crosslinkers, in vivo and ex-vivo. We established that actin crosslinkers readily exchange within the highly stable F-actin structure of the stereocilia core. In addition, we determined that stereocilia degeneration in mice carrying fascin-2R109H mutation and espin null mice could possibly occur due to a less stable actin core. These studies suggest that dynamic crosslinks stabilize the core to maintain proper stereocilia functioning. Future work warrants understanding the reason behind the importance of dynamic crosslinks within a stable stereocilia core. Actin stability not only depends on actin crosslinkers, but also on actin filament composition as evident from distinct stereocilia degeneration and progressive hearing loss patterns in hair-cell specific knockout of actin isoforms. Although beta- and gamma- actin polypeptide sequences differ by only 14 four amino acids, whether the latter determine the unique function of each cytoplasmic actin isoform was previously unknown. Here we determined that these four critical amino acids determine the unique functional importance of beta-actin isoform in sensory hair cells. Taken together, our study demonstrates that actin cytoskeletal proteins are important for the morphogenesis and
maintenance of stereocilia.
McGrath, Jamis. "The role of ADF and cofilin in auditory sensory cell development." Thesis, 2020. http://hdl.handle.net/1805/24883.
Full textOur ability to hear relies on sensory cells found in the inner ear that transduce sound into biological signals. Microvilli-like protrusions called stereocilia are bundled on the apical surfaces of these cells and allow them to respond to sound-evoked vibrations. The architecture of the stereocilia bundle is highly patterned to ensure normal hearing. Filaments of polymerized actin proteins are bundled in parallel into large cylindrical structures that define the dimensions of stereocilia. This network is then anchored to the cell by inserting into another actin-based structure called the cuticular plate, which forms a gel-like structure and facilitates the mechanical properties of the bundle. The shape of the bundle is determined through tissue-level and intrinsic polarization signaling pathways. Auditory brainstem-evoked response testing, immunofluorescence imaging, scanning electron microscopy, and biochemical labeling techniques were used to study how the ADF/cofilin family of actin filament severing and depolymerizing proteins contributes to the development of the stereocilia bundle. Loss of these proteins disrupts the normal bundle patterning process, changes the lengths and widths of stereocilia, and alters the regulation of filament ends near the ion channel at stereocilia tips that is responsible for mechanotransduction. The activity of this channel regulates ADF/cofilins and the actin at stereocilia tips. Aberrant actin growth in actin networks beneath the stereocilia bundle influences the bundle patterning process, causes dysmorphic bundles to form. This work identifies that ADF/cofilins are necessary during auditory sensory cell development to facilitate normal bundle patterning and establishes this protein family as a molecular link between mechanotransduction and stereocilia bundle maturation.