There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may...There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may provide knowledge for overcoming the existing limitations to both the diagnosis and treatment of inner ear diseases. Novel techniques have improved the efficacy of drug delivery and targeting to the inner ear, as well as the quality and accuracy of imaging this structure. In this review, we will describe the pathways and biological barriers of the inner ear regarding drug delivery, the beneficial applications and limitations of the imaging techniques available for inner ear research, the behavior of engineered nanomaterials in inner ear applications, and future perspectives for nanomedicine-based inner ear imaging.展开更多
In this study,I focused on finding a mean of protecting against hearing loss.By infusing the cochlea with the neurotrophin factor,NT-3 alone or combined treatment with MK 801,a NMDA receptor antagonist I found hearing...In this study,I focused on finding a mean of protecting against hearing loss.By infusing the cochlea with the neurotrophin factor,NT-3 alone or combined treatment with MK 801,a NMDA receptor antagonist I found hearing loss was attenuated and spiral ganglion neuron loss was nearly totally protected indicating that the importance of the combined treatment of NT-3 and NMDA receptor antagonists in the treatment of hearing disorders.展开更多
K^(+)cycling in the cochlea is critical to maintain hearing.Many sodium-potassium pumps are proved to participate in K^(+)cycling,such as Na/K-ATPase.Theα2-Na/K-ATPase is an important isoform of Na/K-ATPase.The expre...K^(+)cycling in the cochlea is critical to maintain hearing.Many sodium-potassium pumps are proved to participate in K^(+)cycling,such as Na/K-ATPase.Theα2-Na/K-ATPase is an important isoform of Na/K-ATPase.The expression ofα2-Na/K-ATPase in the cochlea is not clear.In this study,we used C57BL/6 mice as a model of presbycusis and implemented immunohistochemistry staining and quantitative real time-PCR,and theα2-Na/K-ATPase expression pattern was confirmed in the inner ear.It was foundα2-Na/K-ATPase was expressed widely in cochlea and its mRNA and protein expression was gradually reduced with aging(4-,14-,26-and 48-weeks old mice).We suspected that,the down-regulation ofα2-Na/K-ATPase expression might be associated with the remodeling of K^(+)cycling,degeneration of morphological structure and decrease of hearing function in aging C57 mice.In conclusion,we speculated that the reduction ofα2-Na/K-ATPase might play an important role in the pathogenesis of age-related hearing loss.展开更多
Columnar outer hair cells of the inner ear form V-shaped bundles, which are arranged in three rows in the cochlea. If the formation of these V-shaped bundles is disturbed, sensorineural hearing loss occurs. To quantif...Columnar outer hair cells of the inner ear form V-shaped bundles, which are arranged in three rows in the cochlea. If the formation of these V-shaped bundles is disturbed, sensorineural hearing loss occurs. To quantify the distribution of V-shaped bundles, the use of a Turing-type reaction-diffusion (RD) system, including anisotropic diffusion, should be considered. We found that a periodic triangle pattern appears based on the anisotropy in the RD system. Then, using the proposed RD system, the image of the V-shaped bundle was examined. The results showed that the correlation between the RD pattern and V-shape bundles not only classifies the experimental result but also significantly differs in the number of directional changes in a set of V-shape bundle. Therefore, this process can help quantify the images of V-shaped bundles.展开更多
Hair cells in the mammalian inner ear are very fragile and are often injured as a result of acoustic trauma or exposure to ototoxic drugs (cisplatin, aminoglycosides, etc) [1]. In amphibians and birds, spontaneous
miRNA-183 family, in normal biology, is expressed in a harmonious and stable manner in the neurosensory organs and cells. Studies have also shown that miRNA-183 family, in different pathways, affects the neurosensory ...miRNA-183 family, in normal biology, is expressed in a harmonious and stable manner in the neurosensory organs and cells. Studies have also shown that miRNA-183 family, in different pathways, affects the neurosensory development, maintenance, survival and function. In addition, it has potential neuroprotective effects in response to neurosensory destructive stimulations. miRNA-96 mutation causes hereditary deafness in humans and mice, and therefore affects the inner ear activity and its maintenance. Certain roles have been identified for mi R-96 in the maintenance and function of the inner ear. The comparison of the target genes of family-183 in transcriptomes of newborn and adult hair cells shows that hundreds of target genes in this family may affect development and maintenance of the ears. Identifying the genes that are regulated by miRNA-183 family provides researchers with important information about the complex development and environmental regulation of the inner ear, and can offer new approaches to the maintenance and regeneration of hair cells and auditory nerve.展开更多
Infants with congenital deafness caused by severe bilateral inner ear malformations frequently suffer from severe hearing loss and poor balance. Unfortunately, the use of hearing aids is usually ineffective in recover...Infants with congenital deafness caused by severe bilateral inner ear malformations frequently suffer from severe hearing loss and poor balance. Unfortunately, the use of hearing aids is usually ineffective in recovering hearing, necessitating cochlear implants. We report a case of a 6-year-old boy with congenital deafness and bilateral inner ear malformations(right side, incomplete partition type I [IP-I]; left side, common cavity deformity). Hearing aids had a remarkable effect in this patient, enabling sufficient and favorable hearing recovery such as to allow the patient to engage in daily conversations. Per-rotatory nystagmus was recorded on an electronystagmogram for both right and left rotations in a damped rotational chair test. It is rare for deaf children with severe bilateral inner ear malformation to demonstrate favorable development in hearing and good equilibrium function. Our findings suggest that auditoryevestibular hair cells in this patient may have been partially preserved despite IP-I in the right ear and common cavity deformity of the left ear.展开更多
Autoimmune inner ear disease(AIED) represents a very fertile research field and the advancements in the understanding of this disease have a direct application not only in patients affected with this condition but als...Autoimmune inner ear disease(AIED) represents a very fertile research field and the advancements in the understanding of this disease have a direct application not only in patients affected with this condition but also in other inner ear disorders that share the same injury mechanism, damage to the inner ear hair cells. AIED also presents many challenges that have still to be overcome. Firstly, access to the inner ear is limited, as many interventions such as biopsies can result in great irreversible damage. Secondly, there are no completely specific markers for AIED. Lack of a definitive diagnosis can result in the treatment of patients not affected with the disease and, therefore, no response. Finally, some patients become refractory to glucocorticoids and new therapies are needed. This review offers an overview of the animal models that have contributed to the understanding of AIED pathophysiology, the value of currently available diagnostic tests, and therapeutic options, with a special focus on new therapies for non responders or patients refractory to glucocorticoids. Among these new options for therapy, biological agents have been tested recently, whereas gene and stem celltherapy may have a role in the future. The intratympanic route of administration avoids the systemic side effects associated with currently used drugs, and may become a more frequent approach in the future.展开更多
Loss of postnatal mammalian auditory hair cells (HCs) is irreversible. Earlier studies have highlighted the importance of the Retinoblastoma family of proteins (pRBs) (i.e., Rb1, Rbl1/p107, and Rbl2/p130) in the audit...Loss of postnatal mammalian auditory hair cells (HCs) is irreversible. Earlier studies have highlighted the importance of the Retinoblastoma family of proteins (pRBs) (i.e., Rb1, Rbl1/p107, and Rbl2/p130) in the auditory cells’ proliferation and emphasized our lack of information on their specific roles in the auditory system. We have previously demonstrated that lack of Rbl2/p130 moderately affects HCs’ and supporting cells’ (SCs) proliferation. Here, we present evidence supporting multiple roles for Rbl1/p107 inthe developing and mature mouse organ of Corti (OC). Like other pRBs, Rbl1/p107 is expressed in the OC, particularly in the Hensen’s and Deiters’ cells. Moreover, Rbl1/p107 impacts maturation and postmitotic quiescence of HCs and SCs, as evidenced by enhanced numbers of these cells and the presence of dividing cells in the postnatal Rbl1/p107-/-OC. These findings were further supported by microarray and bioinformatics analyses, suggesting downregulation of several bHLH molecules, as well as activation of the Notch/Hes/Hey signaling pathway in homozygous Rbl1/p107 mutant mice. Physiological assessments and detection of ectopic HC marker expression in postnatal spiral ganglion neurons (SGNs) provided evidence for incomplete cell maturation and differentiation in Rbl1/p107﹣/﹣OC. Collectively, the present study highlights an important role for Rbl1/p107 inOC cell differentiation and maturation, which is distinct from other pRBs.展开更多
Objective:To evaluate the plasma levels of the otoconial proteins,otoconin-90 and otolin-1,in individuals diagnosed with vestibular neuritis(VN)and determine the feasibility of using these proteins as biomarkers for V...Objective:To evaluate the plasma levels of the otoconial proteins,otoconin-90 and otolin-1,in individuals diagnosed with vestibular neuritis(VN)and determine the feasibility of using these proteins as biomarkers for VN.Methods:In this preliminary study,30 patients diagnosed with VN and 70 healthy individuals were recruited and followed to confirm whether they had benign paroxysmal positional vertigo(BPPV)during the following time.The recorded data included measurements of height,weight,and history of diabetes mellitus or hypertension.Additionally,levels of plasma otoconin-90,and otolin-1 were measured and compared.Results:The plasma concentrations of otoconin-90 and otolin-1 may not be significantly different between patients with VN and healthy controls,nor among patients with BPPV secondary to VN and patients with VN without BPPV.Conclusions:Plasma otoconin-90 and otolin-1 levels may not serve as biomarkers of acute VN episodes or predict BPPV occurrence secondary to VN.展开更多
Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and e...Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and evaluate therapeutic outcomes,appropriate animal models are necessary.Pigs have been extensively used as valuable large animal models in biomedical research.In this review,we highlight the advantages of pig models in terms of ear anatomy,inner ear morphology,and electrophysiological characteristics,as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss.Additionally,we discuss the prospects,challenges,and recommendations regarding the use pig models in HHL research.Overall,this review provides insights and perspectives for future studies on HHL using porcine models.展开更多
Objective:To describe the characteristics of the clinical presentation,diagnosis,surgical methods,and outcomes of patients with otogenic cerebrospinal fluid(CSF)leakage secondary to congenital inner ear dysplasia.Meth...Objective:To describe the characteristics of the clinical presentation,diagnosis,surgical methods,and outcomes of patients with otogenic cerebrospinal fluid(CSF)leakage secondary to congenital inner ear dysplasia.Methods:A retrospective review was performed of 18 patients with otogenic CSF leakage secondary to inner ear dysplasia who underwent surgery in our group from 2007 to 2017 and had a follow-up of at least 4 months.The average length of follow-up was three years.The characteristics of the clinical presentations of all patients,such as self-reported symptoms,radiographic findings,surgical approaches and methods of repair,position of the leakage during surgery,and postoperative course,including the success rate of surgery,are presented.Results:The patients presented mostly with typical symptoms of meningitis,severe hearing impairment,and CSF otorrhea or rhinorrhea.All 18 patients had at least one previous episode of meningitis accompanied by a severe hearing impairment.The preoperative audiograms of 17 patients showed profound sensorineural hearing loss,and one patient had conductive hearing loss.Twelve patients presented with an initial onset of otorrhea,and two had accompanying rhinorrhea.Six patients complained of rhinorrhea,two of whom were misdiagnosed with CSF rhinorrhea and underwent transnasal endoscopy at another hospital.High-resolution computed tomography(HRCT)images can reveal developments in the inner ear,such as expansion of a vestibular cyst,unclear structure of the semicircular canal or cochlea,or signs of effusion in the middle ear or mastoid,which strongly suggest the possibility of CSF otorrhea.The children in the study suffered more severe dysplasia than adults.All 18 patients had CSF leakage identified during surgery.The most common defect sites were in the stapes footplates(55.6%),and 38.9%of patients had a leak around the oval window.One patient had a return of CSF otorrhea during the postoperative period,which did not re-occur following a second repair.Conclusions:CSF otorrhea due to congenital inner ear dysplasia is more severe in children than in adults.The most common symptoms were meningitis,hearing impairment,and CSF otorrhea or rhinorrhea.HRCT has high diagnostic accuracy for this disease.The most common fistula site was around the oval window,including the stapes footplates and the annular ligament.展开更多
For many years,drug delivery to the inner ear has been a challenge to physicians in the treatment of inner ear disorders.In the past decade,the field of inner ear drug delivery has emerged with the development of new ...For many years,drug delivery to the inner ear has been a challenge to physicians in the treatment of inner ear disorders.In the past decade,the field of inner ear drug delivery has emerged with the development of new biomaterials and drug delivery technologies to improve the effectiveness of inner ear drug therapy.This paper reviews a number of inner ear drug delivery strategies including systemic,intratympanic,and intracochlear delivery.A focus of this review is the recent advances in intratympanic delivery of medications;approaches utilizing novel biomaterials as well as other recent developments are also discussed.Biotechnology-based approaches,such as gene and stem cell therapy methods are also reviewed.Among the various strategies,local drug delivery approaches including intratympanic and intracochlear drug delivery methods that limit systemic exposure are particularly promising.These inner ear drug delivery systems provide a new opportunity to improve the treatment of inner ear disorders.展开更多
Bone morphogenetic proteins(BMPs)are the largest subfamily of the transforming growth factor-βsuperfamily,and they play important roles in the development of numerous organs,including the inner ear.The inner ear is a...Bone morphogenetic proteins(BMPs)are the largest subfamily of the transforming growth factor-βsuperfamily,and they play important roles in the development of numerous organs,including the inner ear.The inner ear is a relatively small organ but has a highly complex structure and is involved in both hearing and balance.Here,we discuss BMPs and BMP signaling pathways and then focus on the role of BMP signal pathway regulation in the development of the inner ear and the implications this has for the treatment of human hearing loss and balance dysfunction.展开更多
Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells(HCs)and supporting cells during mouse inner ear development;however,the relationship be...Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells(HCs)and supporting cells during mouse inner ear development;however,the relationship between the two signaling pathways in the mouse cochlea remains largely unknown.Here,we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5+progenitors during different cochlear development stages.We found that the downregulation of Notch1 in Lgr5+cells from embryonic day(E)14.5 to E18.5 can drive the quiescent Lgr5+cells to re-enter the cell cycle and differentiate into extra HCs,whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells.No effect was observed on the upregulation or downregulation of Notch1 in Lgr5+cells from E10.5 to E14.5.We concluded that the roles of Notch1 in Wnt-responsive Lgr5+cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5+progenitor activation during cochlear differentiation.Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.展开更多
Congenital hearing loss is a common disorder worldwide.Heterogeneous gene variation accounts for approximately 20-25%of such patients.We investigated a five-generation Chinese family with autosomaldominant nonsyndromi...Congenital hearing loss is a common disorder worldwide.Heterogeneous gene variation accounts for approximately 20-25%of such patients.We investigated a five-generation Chinese family with autosomaldominant nonsyndromic sensorineural hearing loss(SNHL).No wave was detected in the pure-tone audiometry,and the auditory brainstem response was absent in all patients.Computed tomography of the patients,as well as of two sporadic SNHL cases,showed bilateral inner ear anomaly,cochlear maldevelopment,absence of the osseous spiral lamina,and an enlarged vestibular aqueduct.Such findings were absent in nonaffected persons.We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4 KB gene(p.Gln121 Arg)encoding phosphatidylinositol 4-kinaseβ(PI4 KB)from the patients in this family.In addition,3 missense PI4 KB(p.Val434 Gly,p.Glu667 Lys,and p.Met739 Arg)mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases.No such mutations were present within 600 Chinese controls,the 1000 genome project,gnom AD,or similar databases.Depleting pi4 kb m RNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment,mimicking the patient phenotypes.Moreover,overexpression of 4 human missense PI4 KB mutant m RNAs in zebrafish embryos resulted in impaired hearing function,suggesting dominant-negative effects.Taken together,our results reveal that PI4 KB mutations can cause SNHL and inner ear malformation.PI4 KB should be included in neonatal deafness screening.展开更多
Auditory function in vertebrates depends on the transduction of sound vibrations into electrical signals by inner ear hair cells.In general,hearing loss resulting from hair cell damage is irreversible because the huma...Auditory function in vertebrates depends on the transduction of sound vibrations into electrical signals by inner ear hair cells.In general,hearing loss resulting from hair cell damage is irreversible because the human ear has been considered to be incapable of regenerating or repairing these sensory elements following severe injury.Therefore,regeneration and protection of inner ear hair cells have become an exciting,rapidly evolving field of research during the last decade.However,mammalian auditory hair cells are few in number,experimentally inaccessible,and barely proliferate postnatally in vitro.Various in vitro primary culture systems of inner ear hair cells have been established by different groups,although many challenges remain unresolved.Here,we briefly explain the structure of the inner ear,summarize the published methods of in vitro hair cell cultures,and propose a feasible protocol for culturing these cells,which gave satisfactory results in our study.A better understanding of in vitro hair cell cultures will substantially facilitate research involving auditory functions,drug development,and the isolation of critical molecules involved in hair cell biology.展开更多
Objective:The zebrafish is an excellent model for studying gene function in auditory system development.Pou4f3 plays an important role in mouse hair cell formation.Here,we constructed apou4f3-knockoutTg(Brn3c:GFP)zebr...Objective:The zebrafish is an excellent model for studying gene function in auditory system development.Pou4f3 plays an important role in mouse hair cell formation.Here,we constructed apou4f3-knockoutTg(Brn3c:GFP)zebrafish to provide an efficient fluorescence-visualized model for studying the molecular mechanisms of ear development.Methods:Cas9/single guide RNAs targeting exon 2 ofpou4f3 were designed and injected into one-cell stage zebrafish embryos(G0 generation).The G0 generation were crossed withTg(Brn3c:GFP)zebrafish to obtainpou4f3-mutantTg(Brn3c:GFP)zebrafish.The targeting efficiency was detected by polymerase chain reaction amplification and Sanger sequencing.Zebrafish hair cells were observed by laser scanning confocal microscopyin vivo.The morphology of the otoliths and semicircular canals were analyzed.All animal experiments were approved by the Animal Care and Use Committee of Shandong Provincial Hospital,Cheeloo College of Medicine,Shandong University(approval No.2016-KY-040)on March 3,2016.Results:Thepou4f3-mutantTg(Brn3c:GFP)zebrafish line was successfully established.Fluorescence observation suggested that hair cell development was delayed inpou4f3-knockout zebrafish.Knockout ofpou4f3 also induced defects in the otoliths and semicircular canals and impaired ear function in zebrafish.Conclusion:A CRISPR/Cas9-mediatedpou4f3 mutantTg(Brn3c:GFP)zebrafish model was established for the first time to demonstrate the essential role ofpou4f3 in zebrafish ear development.Our study provides a highly efficient method for the establishment of a visualized model of gene knockout zebrafish and has the potential to allow high-throughput drug screening to explore therapeutics for related diseases.展开更多
Twenty-four guinea pigs with normal Preyer's reflex were exposed to the octave bands of noise centered at 63 Hz and 4 kHz, 110 dB SPL. The duration of exposure was 4 and 8 hours respectively. The permanent shift o...Twenty-four guinea pigs with normal Preyer's reflex were exposed to the octave bands of noise centered at 63 Hz and 4 kHz, 110 dB SPL. The duration of exposure was 4 and 8 hours respectively. The permanent shift of the guinea pigs at the above two frequencies was at 4-8 kHz. As the duration of exposure were 4 hours, the threshold shift at 63 Hz was smaller than that at 4 kHz. But as the duration of exposure was 8 hours, the threshold shift at 63 Hz and 4 kHz was almost the same. No morphological change of the inner ear was observed in the guinea pigs exposed for 4 hours at the octave bands of noise centered at 63 Hz and 4 kHz, but ultrastruetural abnormalities were noted. After the animals were exposed for 8 hours, morphological, nltrastructural changes in the inner ear were observed. The main pathologic changes were seen at the second torn of the cochlea. These changes in hearing physiology and pathology suggest that a high intensive low frequency noise can result in high frequency hearing loss and that the use of A-weighted levels of specific damage risk criteria for noise sources may be inappropriate.展开更多
基金supported by the National Natural Science Foundation of China(grant number:81170914/H1304)
文摘There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may provide knowledge for overcoming the existing limitations to both the diagnosis and treatment of inner ear diseases. Novel techniques have improved the efficacy of drug delivery and targeting to the inner ear, as well as the quality and accuracy of imaging this structure. In this review, we will describe the pathways and biological barriers of the inner ear regarding drug delivery, the beneficial applications and limitations of the imaging techniques available for inner ear research, the behavior of engineered nanomaterials in inner ear applications, and future perspectives for nanomedicine-based inner ear imaging.
文摘In this study,I focused on finding a mean of protecting against hearing loss.By infusing the cochlea with the neurotrophin factor,NT-3 alone or combined treatment with MK 801,a NMDA receptor antagonist I found hearing loss was attenuated and spiral ganglion neuron loss was nearly totally protected indicating that the importance of the combined treatment of NT-3 and NMDA receptor antagonists in the treatment of hearing disorders.
基金National Natural Science Foundation of China(Nos.81771004,81271078,81500791,81500794 and 81300827).
文摘K^(+)cycling in the cochlea is critical to maintain hearing.Many sodium-potassium pumps are proved to participate in K^(+)cycling,such as Na/K-ATPase.Theα2-Na/K-ATPase is an important isoform of Na/K-ATPase.The expression ofα2-Na/K-ATPase in the cochlea is not clear.In this study,we used C57BL/6 mice as a model of presbycusis and implemented immunohistochemistry staining and quantitative real time-PCR,and theα2-Na/K-ATPase expression pattern was confirmed in the inner ear.It was foundα2-Na/K-ATPase was expressed widely in cochlea and its mRNA and protein expression was gradually reduced with aging(4-,14-,26-and 48-weeks old mice).We suspected that,the down-regulation ofα2-Na/K-ATPase expression might be associated with the remodeling of K^(+)cycling,degeneration of morphological structure and decrease of hearing function in aging C57 mice.In conclusion,we speculated that the reduction ofα2-Na/K-ATPase might play an important role in the pathogenesis of age-related hearing loss.
文摘Columnar outer hair cells of the inner ear form V-shaped bundles, which are arranged in three rows in the cochlea. If the formation of these V-shaped bundles is disturbed, sensorineural hearing loss occurs. To quantify the distribution of V-shaped bundles, the use of a Turing-type reaction-diffusion (RD) system, including anisotropic diffusion, should be considered. We found that a periodic triangle pattern appears based on the anisotropy in the RD system. Then, using the proposed RD system, the image of the V-shaped bundle was examined. The results showed that the correlation between the RD pattern and V-shape bundles not only classifies the experimental result but also significantly differs in the number of directional changes in a set of V-shape bundle. Therefore, this process can help quantify the images of V-shaped bundles.
基金supported by the follow grants:1. The StateKey Program of National Natural Science of China (Grant No. 30730040)2. The National High Technology Research and Development Program of China (Grant No.2007AA02Z150)+2 种基金3. The National Natural Science Foundation of China (30871398)Key Projects in the National Science & Technology Supporting Program during the Eleventh Five-Year Plan Period (2008BAI50B08 2007 BAI18B12, 2007BAI18B14)
文摘Hair cells in the mammalian inner ear are very fragile and are often injured as a result of acoustic trauma or exposure to ototoxic drugs (cisplatin, aminoglycosides, etc) [1]. In amphibians and birds, spontaneous
文摘miRNA-183 family, in normal biology, is expressed in a harmonious and stable manner in the neurosensory organs and cells. Studies have also shown that miRNA-183 family, in different pathways, affects the neurosensory development, maintenance, survival and function. In addition, it has potential neuroprotective effects in response to neurosensory destructive stimulations. miRNA-96 mutation causes hereditary deafness in humans and mice, and therefore affects the inner ear activity and its maintenance. Certain roles have been identified for mi R-96 in the maintenance and function of the inner ear. The comparison of the target genes of family-183 in transcriptomes of newborn and adult hair cells shows that hundreds of target genes in this family may affect development and maintenance of the ears. Identifying the genes that are regulated by miRNA-183 family provides researchers with important information about the complex development and environmental regulation of the inner ear, and can offer new approaches to the maintenance and regeneration of hair cells and auditory nerve.
文摘Infants with congenital deafness caused by severe bilateral inner ear malformations frequently suffer from severe hearing loss and poor balance. Unfortunately, the use of hearing aids is usually ineffective in recovering hearing, necessitating cochlear implants. We report a case of a 6-year-old boy with congenital deafness and bilateral inner ear malformations(right side, incomplete partition type I [IP-I]; left side, common cavity deformity). Hearing aids had a remarkable effect in this patient, enabling sufficient and favorable hearing recovery such as to allow the patient to engage in daily conversations. Per-rotatory nystagmus was recorded on an electronystagmogram for both right and left rotations in a damped rotational chair test. It is rare for deaf children with severe bilateral inner ear malformation to demonstrate favorable development in hearing and good equilibrium function. Our findings suggest that auditoryevestibular hair cells in this patient may have been partially preserved despite IP-I in the right ear and common cavity deformity of the left ear.
文摘Autoimmune inner ear disease(AIED) represents a very fertile research field and the advancements in the understanding of this disease have a direct application not only in patients affected with this condition but also in other inner ear disorders that share the same injury mechanism, damage to the inner ear hair cells. AIED also presents many challenges that have still to be overcome. Firstly, access to the inner ear is limited, as many interventions such as biopsies can result in great irreversible damage. Secondly, there are no completely specific markers for AIED. Lack of a definitive diagnosis can result in the treatment of patients not affected with the disease and, therefore, no response. Finally, some patients become refractory to glucocorticoids and new therapies are needed. This review offers an overview of the animal models that have contributed to the understanding of AIED pathophysiology, the value of currently available diagnostic tests, and therapeutic options, with a special focus on new therapies for non responders or patients refractory to glucocorticoids. Among these new options for therapy, biological agents have been tested recently, whereas gene and stem celltherapy may have a role in the future. The intratympanic route of administration avoids the systemic side effects associated with currently used drugs, and may become a more frequent approach in the future.
文摘Loss of postnatal mammalian auditory hair cells (HCs) is irreversible. Earlier studies have highlighted the importance of the Retinoblastoma family of proteins (pRBs) (i.e., Rb1, Rbl1/p107, and Rbl2/p130) in the auditory cells’ proliferation and emphasized our lack of information on their specific roles in the auditory system. We have previously demonstrated that lack of Rbl2/p130 moderately affects HCs’ and supporting cells’ (SCs) proliferation. Here, we present evidence supporting multiple roles for Rbl1/p107 inthe developing and mature mouse organ of Corti (OC). Like other pRBs, Rbl1/p107 is expressed in the OC, particularly in the Hensen’s and Deiters’ cells. Moreover, Rbl1/p107 impacts maturation and postmitotic quiescence of HCs and SCs, as evidenced by enhanced numbers of these cells and the presence of dividing cells in the postnatal Rbl1/p107-/-OC. These findings were further supported by microarray and bioinformatics analyses, suggesting downregulation of several bHLH molecules, as well as activation of the Notch/Hes/Hey signaling pathway in homozygous Rbl1/p107 mutant mice. Physiological assessments and detection of ectopic HC marker expression in postnatal spiral ganglion neurons (SGNs) provided evidence for incomplete cell maturation and differentiation in Rbl1/p107﹣/﹣OC. Collectively, the present study highlights an important role for Rbl1/p107 inOC cell differentiation and maturation, which is distinct from other pRBs.
基金supported by the Ningbo Leading Medical&Health Discipline(Grant No.2022-B12)Ningbo Natural Science Foundation(Grant No.202003N4240)+1 种基金Hwa Mei Foundation(Grant No.2021HMZY102,Grant No.2022HMKY45)Medical Scientific Research Foundation of Zhejiang Province(Grant No.2023KY1085).
文摘Objective:To evaluate the plasma levels of the otoconial proteins,otoconin-90 and otolin-1,in individuals diagnosed with vestibular neuritis(VN)and determine the feasibility of using these proteins as biomarkers for VN.Methods:In this preliminary study,30 patients diagnosed with VN and 70 healthy individuals were recruited and followed to confirm whether they had benign paroxysmal positional vertigo(BPPV)during the following time.The recorded data included measurements of height,weight,and history of diabetes mellitus or hypertension.Additionally,levels of plasma otoconin-90,and otolin-1 were measured and compared.Results:The plasma concentrations of otoconin-90 and otolin-1 may not be significantly different between patients with VN and healthy controls,nor among patients with BPPV secondary to VN and patients with VN without BPPV.Conclusions:Plasma otoconin-90 and otolin-1 levels may not serve as biomarkers of acute VN episodes or predict BPPV occurrence secondary to VN.
基金supported by the National Key Research and Development Program of China (2021YFA0805902,2022YFF0710703)National Natural Science Foundation of China (32201257)+1 种基金Science and Technology Innovation Project of Xiongan New Area (2022XAGG0121)Young Elite Scientists Sponsorship Program by the China Association for Science and Technology (2019QNRC001)。
文摘Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and evaluate therapeutic outcomes,appropriate animal models are necessary.Pigs have been extensively used as valuable large animal models in biomedical research.In this review,we highlight the advantages of pig models in terms of ear anatomy,inner ear morphology,and electrophysiological characteristics,as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss.Additionally,we discuss the prospects,challenges,and recommendations regarding the use pig models in HHL research.Overall,this review provides insights and perspectives for future studies on HHL using porcine models.
基金Project supported by the National Natural Science Foundation of China(Nos.81570914 and 81700925)
文摘Objective:To describe the characteristics of the clinical presentation,diagnosis,surgical methods,and outcomes of patients with otogenic cerebrospinal fluid(CSF)leakage secondary to congenital inner ear dysplasia.Methods:A retrospective review was performed of 18 patients with otogenic CSF leakage secondary to inner ear dysplasia who underwent surgery in our group from 2007 to 2017 and had a follow-up of at least 4 months.The average length of follow-up was three years.The characteristics of the clinical presentations of all patients,such as self-reported symptoms,radiographic findings,surgical approaches and methods of repair,position of the leakage during surgery,and postoperative course,including the success rate of surgery,are presented.Results:The patients presented mostly with typical symptoms of meningitis,severe hearing impairment,and CSF otorrhea or rhinorrhea.All 18 patients had at least one previous episode of meningitis accompanied by a severe hearing impairment.The preoperative audiograms of 17 patients showed profound sensorineural hearing loss,and one patient had conductive hearing loss.Twelve patients presented with an initial onset of otorrhea,and two had accompanying rhinorrhea.Six patients complained of rhinorrhea,two of whom were misdiagnosed with CSF rhinorrhea and underwent transnasal endoscopy at another hospital.High-resolution computed tomography(HRCT)images can reveal developments in the inner ear,such as expansion of a vestibular cyst,unclear structure of the semicircular canal or cochlea,or signs of effusion in the middle ear or mastoid,which strongly suggest the possibility of CSF otorrhea.The children in the study suffered more severe dysplasia than adults.All 18 patients had CSF leakage identified during surgery.The most common defect sites were in the stapes footplates(55.6%),and 38.9%of patients had a leak around the oval window.One patient had a return of CSF otorrhea during the postoperative period,which did not re-occur following a second repair.Conclusions:CSF otorrhea due to congenital inner ear dysplasia is more severe in children than in adults.The most common symptoms were meningitis,hearing impairment,and CSF otorrhea or rhinorrhea.HRCT has high diagnostic accuracy for this disease.The most common fistula site was around the oval window,including the stapes footplates and the annular ligament.
文摘For many years,drug delivery to the inner ear has been a challenge to physicians in the treatment of inner ear disorders.In the past decade,the field of inner ear drug delivery has emerged with the development of new biomaterials and drug delivery technologies to improve the effectiveness of inner ear drug therapy.This paper reviews a number of inner ear drug delivery strategies including systemic,intratympanic,and intracochlear delivery.A focus of this review is the recent advances in intratympanic delivery of medications;approaches utilizing novel biomaterials as well as other recent developments are also discussed.Biotechnology-based approaches,such as gene and stem cell therapy methods are also reviewed.Among the various strategies,local drug delivery approaches including intratympanic and intracochlear drug delivery methods that limit systemic exposure are particularly promising.These inner ear drug delivery systems provide a new opportunity to improve the treatment of inner ear disorders.
基金Project Project supported by the National Key Technologies R&D Program of China(Nos.2017YFA0103900 and 2016YFC0905200)the National Natural Science Foundation of China(Nos.81620108005,8177040802,and 81622013)the Shanghaigng Talents Plan(No.18PJ1401700),China
文摘Bone morphogenetic proteins(BMPs)are the largest subfamily of the transforming growth factor-βsuperfamily,and they play important roles in the development of numerous organs,including the inner ear.The inner ear is a relatively small organ but has a highly complex structure and is involved in both hearing and balance.Here,we discuss BMPs and BMP signaling pathways and then focus on the role of BMP signal pathway regulation in the development of the inner ear and the implications this has for the treatment of human hearing loss and balance dysfunction.
基金This work was supported by the National Key R&D Program of China(No.2017YFA0103900)the National Natural Science Foundation of China(Nos.81771011,81771010,81700910,81700914,and 81400463)+2 种基金the Development Fund for Shanghai Talents(No.2017046)the Excellent Personnel Training Plan for Shanghai Health System(No.2017Q003)the Shanghai HFPC Foundation(No.201440402).
文摘Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells(HCs)and supporting cells during mouse inner ear development;however,the relationship between the two signaling pathways in the mouse cochlea remains largely unknown.Here,we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5+progenitors during different cochlear development stages.We found that the downregulation of Notch1 in Lgr5+cells from embryonic day(E)14.5 to E18.5 can drive the quiescent Lgr5+cells to re-enter the cell cycle and differentiate into extra HCs,whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells.No effect was observed on the upregulation or downregulation of Notch1 in Lgr5+cells from E10.5 to E14.5.We concluded that the roles of Notch1 in Wnt-responsive Lgr5+cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5+progenitor activation during cochlear differentiation.Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.
基金supported by the grants from the National Key R&D Program of China(2018YFA0801200)the National Natural Science Foundation of China(31970777,31771628,and 31601165)+1 种基金Guangdong Natural Science Fund for Distinguished Young Scholars(2017A030306024)to J.Z.the Deutsche Forschungsgemeinschaft(DFG:GO 1990/1-1)to M.G
文摘Congenital hearing loss is a common disorder worldwide.Heterogeneous gene variation accounts for approximately 20-25%of such patients.We investigated a five-generation Chinese family with autosomaldominant nonsyndromic sensorineural hearing loss(SNHL).No wave was detected in the pure-tone audiometry,and the auditory brainstem response was absent in all patients.Computed tomography of the patients,as well as of two sporadic SNHL cases,showed bilateral inner ear anomaly,cochlear maldevelopment,absence of the osseous spiral lamina,and an enlarged vestibular aqueduct.Such findings were absent in nonaffected persons.We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4 KB gene(p.Gln121 Arg)encoding phosphatidylinositol 4-kinaseβ(PI4 KB)from the patients in this family.In addition,3 missense PI4 KB(p.Val434 Gly,p.Glu667 Lys,and p.Met739 Arg)mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases.No such mutations were present within 600 Chinese controls,the 1000 genome project,gnom AD,or similar databases.Depleting pi4 kb m RNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment,mimicking the patient phenotypes.Moreover,overexpression of 4 human missense PI4 KB mutant m RNAs in zebrafish embryos resulted in impaired hearing function,suggesting dominant-negative effects.Taken together,our results reveal that PI4 KB mutations can cause SNHL and inner ear malformation.PI4 KB should be included in neonatal deafness screening.
基金Project supported by the National Basic Research Priorities Program of China(Nos.2014CB541702 and 2014CB541704)the National Natural Science Foundation of China(No.31671305)
文摘Auditory function in vertebrates depends on the transduction of sound vibrations into electrical signals by inner ear hair cells.In general,hearing loss resulting from hair cell damage is irreversible because the human ear has been considered to be incapable of regenerating or repairing these sensory elements following severe injury.Therefore,regeneration and protection of inner ear hair cells have become an exciting,rapidly evolving field of research during the last decade.However,mammalian auditory hair cells are few in number,experimentally inaccessible,and barely proliferate postnatally in vitro.Various in vitro primary culture systems of inner ear hair cells have been established by different groups,although many challenges remain unresolved.Here,we briefly explain the structure of the inner ear,summarize the published methods of in vitro hair cell cultures,and propose a feasible protocol for culturing these cells,which gave satisfactory results in our study.A better understanding of in vitro hair cell cultures will substantially facilitate research involving auditory functions,drug development,and the isolation of critical molecules involved in hair cell biology.
基金supported by the National Natural Science Foundation of China(Nos.81670942,81470704,and 81972057)Special Funds for Taishan Scholar Project.
文摘Objective:The zebrafish is an excellent model for studying gene function in auditory system development.Pou4f3 plays an important role in mouse hair cell formation.Here,we constructed apou4f3-knockoutTg(Brn3c:GFP)zebrafish to provide an efficient fluorescence-visualized model for studying the molecular mechanisms of ear development.Methods:Cas9/single guide RNAs targeting exon 2 ofpou4f3 were designed and injected into one-cell stage zebrafish embryos(G0 generation).The G0 generation were crossed withTg(Brn3c:GFP)zebrafish to obtainpou4f3-mutantTg(Brn3c:GFP)zebrafish.The targeting efficiency was detected by polymerase chain reaction amplification and Sanger sequencing.Zebrafish hair cells were observed by laser scanning confocal microscopyin vivo.The morphology of the otoliths and semicircular canals were analyzed.All animal experiments were approved by the Animal Care and Use Committee of Shandong Provincial Hospital,Cheeloo College of Medicine,Shandong University(approval No.2016-KY-040)on March 3,2016.Results:Thepou4f3-mutantTg(Brn3c:GFP)zebrafish line was successfully established.Fluorescence observation suggested that hair cell development was delayed inpou4f3-knockout zebrafish.Knockout ofpou4f3 also induced defects in the otoliths and semicircular canals and impaired ear function in zebrafish.Conclusion:A CRISPR/Cas9-mediatedpou4f3 mutantTg(Brn3c:GFP)zebrafish model was established for the first time to demonstrate the essential role ofpou4f3 in zebrafish ear development.Our study provides a highly efficient method for the establishment of a visualized model of gene knockout zebrafish and has the potential to allow high-throughput drug screening to explore therapeutics for related diseases.
文摘Twenty-four guinea pigs with normal Preyer's reflex were exposed to the octave bands of noise centered at 63 Hz and 4 kHz, 110 dB SPL. The duration of exposure was 4 and 8 hours respectively. The permanent shift of the guinea pigs at the above two frequencies was at 4-8 kHz. As the duration of exposure were 4 hours, the threshold shift at 63 Hz was smaller than that at 4 kHz. But as the duration of exposure was 8 hours, the threshold shift at 63 Hz and 4 kHz was almost the same. No morphological change of the inner ear was observed in the guinea pigs exposed for 4 hours at the octave bands of noise centered at 63 Hz and 4 kHz, but ultrastruetural abnormalities were noted. After the animals were exposed for 8 hours, morphological, nltrastructural changes in the inner ear were observed. The main pathologic changes were seen at the second torn of the cochlea. These changes in hearing physiology and pathology suggest that a high intensive low frequency noise can result in high frequency hearing loss and that the use of A-weighted levels of specific damage risk criteria for noise sources may be inappropriate.
