Dataset Information

Key Genes and Pathways Associated With Inner Ear Malformation in SOX10? p.R109W Mutation Pigs.

ABSTRACT: SRY-box 10 (SOX10) mutation may lead to inner ear deformities. However, its molecular mechanisms on inner ear development are not clear. In this work, the inner ear morphology was investigated at different embryonic stages of the SOX10 mutation miniature porcine model with sensorineural hearing loss, and high-throughput RNA-seq and bioinformatics analyses were applied. Our results indicated that the SOX10 mutation in the miniature pigs led to an incomplete partition (IP) of the cochlea, a cystic apex caused by fusion from middle and apical turns, cochlear modiolar defects and a shortened cochlear duct. The model demonstrated 173 differentially expressed genes (DEGs) and 185 differentially expressed long non-coding RNAs (lncRNAs). The down-regulated DEGs most significantly enriched the inflammatory mediator regulation of the TRP channels, arachidonic acid metabolism, and the salivary secretion pathways, while the up-regulated DEGs most significantly enriched the systemic lupus erythematosus and alcoholism pathways. Based on gene cluster analysis, we selected four gene groups: WNT1, KCNQ4, STRC and PAX6.

SUBMITTER: Hao QQ

PROVIDER: S-EPMC5996026 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Key Genes and Pathways Associated With Inner Ear Malformation in SOX10 <sup><i>p.R109W</i></sup> Mutation Pigs.

Hao Qing-Qing QQ Li Liang L Chen Wei W Jiang Qing-Qing QQ Ji Fei F Sun Wei W Wei Hong H Guo Wei-Wei WW Yang Shi-Ming SM

Frontiers in molecular neuroscience 20180605

SRY-box 10 (SOX10) mutation may lead to inner ear deformities. However, its molecular mechanisms on inner ear development are not clear. In this work, the inner ear morphology was investigated at different embryonic stages of the SOX10 mutation miniature porcine model with sensorineural hearing loss, and high-throughput RNA-seq and bioinformatics analyses were applied. Our results indicated that the SOX10 mutation in the miniature pigs led to an incomplete partition (IP) of the cochlea, a cystic ...[more]

PMID: 29922125

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Project description:Introduction: One major obstacle in validating drugs for the treatment or prevention of hearing loss is the limited data available on the distribution and concentration of drugs in the human inner ear. Although small animal models offer some insights into inner ear pharmacokinetics, their smaller organ size and different barrier (round window membrane) permeabilities compared to humans can complicate study interpretation. Therefore, developing a reliable large animal model for inner ear drug delivery is crucial. The inner and middle ear anatomy of domestic pigs closely resembles that of humans, making them promising candidates for studying inner ear pharmacokinetics. However, unlike humans, the anatomical orientation and tortuosity of the porcine external ear canal frustrates local drug delivery to the inner ear. Methods: In this study, we developed a surgical technique to access the tympanic membrane of pigs. To assess hearing pre- and post-surgery, auditory brainstem responses to click and pure tones were measured. Additionally, we performed 3D segmentation of the porcine inner ear images and used this data to simulate the diffusion of dexamethasone within the inner ear through fluid simulation software (FluidSim). Results: We have successfully delivered dexamethasone and dexamethasone sodium phosphate to the porcine inner ear via the intratympanic injection. The recorded auditory brainstem measurements revealed no adverse effects on hearing thresholds attributable to the surgery. We have also simulated the diffusion rates for dexamethasone and dexamethasone sodium phosphate into the porcine inner ear and confirmed the accuracy of the simulations using in-vivo data. Discussion: We have developed and characterized a method for conducting pharmacokinetic studies of the inner ear using pigs. This animal model closely mirrors the size of the human cochlea and the thickness of its barriers. The diffusion time and drug concentrations we reported align closely with the limited data available from human studies. Therefore, we have demonstrated the potential of using pigs as a large animal model for studying inner ear pharmacokinetics.

Dataset Information

Key Genes and Pathways Associated With Inner Ear Malformation in SOX10? p.R109W Mutation Pigs.

Publications

Key Genes and Pathways Associated With Inner Ear Malformation in SOX10 <sup><i>p.R109W</i></sup> Mutation Pigs.

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