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A kinase inhibitor screen identifies signaling pathways regulating mucosal growth during otitis media.

ABSTRACT: Otitis media, the most common disease of childhood, is characterized by extensive changes in the morphology of the middle ear cavity. This includes hyperplasia of the mucosa that lines the tympanic cavity, from a simple monolayer of squamous epithelium into a greatly thickened, respiratory-type mucosa. The processes that control this response, which is critical to otitis media pathogenesis and recovery, are incompletely understood. Given the central role of protein phosphorylation in most intracellular processes, including cell proliferation and differentiation, we screened a library of kinase inhibitors targeting members of all the major families in the kinome for their ability to influence the growth of middle ear mucosal explants in vitro. Of the 160 inhibitors, 30 were found to inhibit mucosal growth, while two inhibitors enhanced tissue proliferation. The results suggest that the regulation of infection-mediated tissue growth in the ME mucosa involves multiple cellular processes that span the kinome. While some of the pathways and processes identified have been previously implicated in mucosa hyperplasia others are novel. The results were used to generate a global model of growth regulation by kinase pathways. The potential for therapeutic applications of the results are discussed.

SUBMITTER: Noel J

PROVIDER: S-EPMC7410257 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Proteomic Study Identifies Glycolytic and Inflammation Pathways Involved in Recurrent Otitis Media.

Project description:Recurrent acute otitis media (RAOM) in children is clinically defined as the occurrence of at least three episodes of acute otitis media over a course of 6 months. A further common pathological condition of interest in the context of pediatric otolaryngology is adenotonsillar hypertrophy (ATH), a common cause of obstructive sleep apnea syndrome. Aimed at unraveling the differential modulation of proteins in the two pathologies and at understanding the possible pathways involved in their onset, we analyzed the proteomic profile of the adenoids from 14 RAOM and ATH patients by using two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). The 2-DE coupled with MS allowed us to identify 23 spots with significant (p-value < 0.05) changes in protein amount, recognizing proteins involved in neutrophil degranulation and glycolysis pathways.

| S-EPMC7731350 | biostudies-literature

A mouse model of otitis media identifies HB-EGF as a mediator of inflammation-induced mucosal proliferation.

Project description:ObjectiveOtitis media is one of the most common pediatric infections. While it is usually treated without difficulty, up to 20% of children may progress to long-term complications that include hearing loss, impaired speech and language development, academic underachievement, and irreversible disease. Hyperplasia of middle ear mucosa contributes to the sequelae of acute otitis media and is of important clinical significance. Understanding the role of growth factors in the mediation of mucosal hyperplasia could lead to the development of new therapeutic interventions for this disease and its sequelae.MethodsFrom a whole genome gene array analysis of mRNA expression during acute otitis media, we identified growth factors with expression kinetics temporally related to hyperplasia. We then tested these factors for their ability to stimulate mucosal epithelial growth in vitro, and determined protein levels and histological distribution in vivo for active factors.ResultsFrom the gene array, we identified seven candidate growth factors with upregulation of mRNA expression kinetics related to mucosal hyperplasia. Of the seven, only HB-EGF (heparin-binding-epidermal growth factor) induced significant mucosal epithelial hyperplasia in vitro. Subsequent quantification of HB-EGF protein expression in vivo via Western blot analysis confirmed that the protein is highly expressed from 6 hours to 24 hours after bacterial inoculation, while immunohistochemistry revealed production by middle ear epithelial cells and infiltrating lymphocytes.ConclusionOur data suggest an active role for HB-EGF in the hyperplasia of the middle ear mucosal epithelium during otitis media. These results imply that therapies targeting HB-EGF could ameliorate mucosal growth during otitis media, and thereby reduce detrimental sequelae of this childhood disease.

| S-EPMC4102546 | biostudies-literature

Otitis media metagenome

Project description:Impact of narrow-spectrum antibiotics on the oral and fecal microbiome and resistome in a young child treated for otitis media

| PRJEB31957 | ENA

A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.

Project description:A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061?+?1?G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.

| S-EPMC6711784 | biostudies-literature

Otitis Media Impact on Ear

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-07-23 | GSE49129 | GEO

A genome-wide association study of chronic otitis media with effusion and recurrent otitis media identifies a novel susceptibility locus on chromosome 2.

Project description:Chronic otitis media with effusion (COME) and recurrent otitis media (ROM) have been shown to be heritable, but candidate gene and linkage studies to date have been equivocal. Our aim was to identify genetic susceptibility factors using a genome-wide association study (GWAS). We genotyped 602 subjects from 143 families with 373 COME/ROM subjects using the Illumina Human CNV370-Duo DNA Bead Chip (324,748 SNPs). We carried out the GWAS scan and imputed SNPs at the regions with the most significant associations. Replication genotyping in an independent family-based sample was conducted for 53 SNPs: the 41 most significant SNPs with P?<?10(-4) and 12 imputed SNPs with P?<?10(-4) on chromosome 15 (near the strongest signal). We replicated the association of rs10497394 (GWAS discovery P?=?1.30?×?10(-5)) on chromosome 2 in the independent otitis media population (P?=?4.7?×?10(-5); meta-analysis P?=?1.52?×?10(-8)). Three additional SNPs had replication P?values?<?0.10. Two were on chromosome 15q26.1 including rs1110060, the strongest association with COME/ROM in the primary GWAS (P?=?3.4?×10(-7)) in KIF7 intron 7 (P?=?0.072), and rs10775247, a non-synonymous SNP in TICRR exon 2 (P?=?0.075). The third SNP rs386057 was on chromosome 5 in TPPP intron 1 (P?=?0.045). We have performed the first GWAS of COME/ROM and have identified a SNP rs10497394 on chromosome 2 is significantly associated with COME/ROM susceptibility. This SNP is within a 537 kb intergenic region, bordered by CDCA7 and SP3. The genomic and functional significance of this newly identified locus in COME/ROM pathogenesis requires additional investigation.

| S-EPMC3825021 | biostudies-literature

A kinase inhibitor screen identifies small-molecule enhancers of reprogramming and iPS cell generation.

Project description:Somatic cells can be reprogrammed to form embryonic stem cell-like induced pluripotent stem cells (iPSCs), but the process suffers from low efficiency and the underlying molecular mechanisms that control reprogramming remain poorly understood. Here we perform an inhibitor screen to identify kinases that enhance, or present a barrier to, reprogramming. In particular, inhibitors of p38, inositol trisphosphate 3-kinase, and Aurora A kinase potently enhance iPSC generation, and iPSCs derived from inhibitor-treated somatic cells are capable of reaching a fully reprogrammed state. Knockdown of target kinases by short interfering RNAs confirms that they function as barrier genes. We show that Aurora A kinase, which functions in centrosome activity and spindle assembly, is highly induced during reprogramming and inhibits Akt-mediated inactivation of GSK3?, resulting in compromised reprogramming efficiency. Together, our results not only identify new compounds that enhance iPSC generation but also shed new light on the function of Aurora A kinase in the reprogramming process.

| S-EPMC3658009 | biostudies-literature

Otitis Media Impact on Middle Ear

Project description:Objective: Otitis media is known to alter expression of cytokine and other genes in the mouse middle ear and inner ear. However, whole mouse genome studies of gene expression in otitis media have not previously been undertaken. Ninety-nine percent of mouse genes are shared in the human, so these studies are relevant to the human condition. Methods: To assess inflammation-driven processes in the mouse ear, gene chip analyses were conducted on mice treated with trans-tympanic heat-killed Hemophilus influenza using untreated mice as controls. Middle and inner ear tissues were separately harvested at 6 hours, RNA extracted, and samples for each treatment processed on the Affymetrix 430 2.0 Gene Chip for expression of its 34,000 genes. Results: Statistical analysis of gene expression compared to control mice showed significant alteration of gene expression in 2,355 genes, 11% of the genes tested and 8% of the mouse genome. Significant middle and inner ear upregulation (fold change >1.5, p<0.05) was seen in 1,081 and 599 genes respectively. Significant middle and inner ear downregulation (fold change <0.67, p<0.05) was seen in 978 and 287 genes respectively. While otitis media is widely believed to be an exclusively middle ear process with little impact on the inner ear, the inner ear changes noted in this study were numerous and discrete from the middle ear responses. This suggests that the inner ear does indeed respond to otitis media and that its response is a distinctive process. Numerous new genes, previously not studied, are found to be affected by inflammation in the ear. Conclusion: Whole genome analysis via gene chip allows simultaneous examination of expression of hundreds of gene families influenced by inflammation in the middle ear. Discovery of new gene families affected by inflammation may lead to new approaches to the study and treatment of otitis media.

2013-07-23 | GSE49128 | GEO

Otitis Media Impact on Inner Ear

2013-07-23 | GSE49122 | GEO

Acute Otitis Media Curriculum.

Project description:IntroductionStudies have shown that clinicians do a poor job of diagnosing middle ear infections, and an inaccurate diagnosis may result in inappropriate treatment, such as overuse of antibiotics. Antibiotic overuse is known to lead to increased bacterial resistance and puts patients at risk of deleterious side effects, including allergic reactions, vomiting, diarrhea, and rash. In this curriculum, we teach three important topics for achieving a successful middle ear exam and diagnosis of pathology.MethodsThe topics covered during the session are middle ear examination techniques, diagnosis of middle ear pathology and criteria for diagnosing acute otitis media, and treatment of acute otitis media. Each topic has a 30-minute lesson plan with broad goals, specific and measurable learning objectives, interactive learning activities, and assessment measures. Teaching activities include a mix of knowledge, skill, and attitude activities. Assessment measures aim at the highest level of Miller's pyramid of assessment when possible. Also included is a scholarship map that relates how this learning activity can fit into the assessment of learners at the program level by linking learning objectives with pediatric developmental milestones.ResultsThe interactive nature of these lessons has been very well received by learners, and pediatric residents have had a self-perceived increase in skills.DiscussionThis curriculum provides a standardized approach to teaching the middle ear exam structured by educational rubrics and allows for accurate assessment of learners.

| S-EPMC6440425 | biostudies-literature

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