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Principal Investigator: Gaurav K Varshney
Organization: OKLAHOMA MEDICAL RESEARCH FOUNDATION
Fiscal Year: 2024
Award: $213,125
Funding agency: National Institute on Deafness and Other Communication Disorders
Hearing loss is a highly prevalent and debilitating neurosensory disorder associated with substantially reduced
quality of life and overall health. It currently affects 430 million people worldwide; by 2050 this is expected to
increase to nearly 2.5 billion and result 1 in 10 people requiring rehabilitation. About 50% of cases are predicted
to have a genetic basis, however hearing loss can also be caused by other factors such as age, ototoxic drugs,
noise, infection or injury. Low-cost next generation sequencing technologies have facilitated many genome-wide
association studies (GWAS) and exome sequencing projects that have identified hundreds of variants and genes
associated with hearing loss. There are currently more than 150 loci and over 100 genes associated with non-
syndromic hearing loss, however few candidate genes have been identified for complex phenotypes such as
age-related hearing loss (ARHL) or
presbycusis, which
is becoming increasingly common as the population
ages. A GWAS conducted to identify candidate genes associated with ARHL identified 44 independent genomic
loci associated with hearing loss. A nearest gene was mapped for each SNP identified in this study, yet how this
SNP influences gene function in hearing loss has not been determined. Establishing a linkage between the target
genes and the disease phenotype is a huge challenge that ultimately affects the correct diagnosis; generating
similar phenotypes upon gene inactivation in animal models can establish a strong support for a candidate gene.
We identified 39 orthologs of 44 GWAS candidate genes in zebrafish, and further selected 29 novel genes that
will be tested functionally for their role in hearing loss by (1) generating a library of zebrafish mutants for 29 (and
paralogs) candidate genes associated with ARHL (2) analyzing these mutants via a high-throughput phenotyping
pipeline including morphological, cellular, and behavioral phenotypes. Identifying the functional consequences
of the candidate genes in zebrafish will yield mechanistic insights in disease pathogenesis.
Terms: <21+ years old><Acoustics><Adult><Adult Human><Affect><Age><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Behavior><Biologic Models><Biological Models><Body Tissues><Brachydanio rerio><CDH23><CDH23 gene><CDHR23><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cadherin-23><Cadherin-Related Family, Member 23><Candidate Disease Gene><Candidate Gene><Cas nuclease technology><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Coloring Agents><Complex><Corti Cell><Danio rerio><Data><Development><Diagnosis><Dimensions><Disease><Disorder><Drug Screening><Drugs><Dyes><Embryo Development><Embryogenesis><Embryonic Development><Ensure><Fertilization><GWA study><GWAS><Gene Inactivation><Gene Silencing><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetics-Mutagenesis><Goals><Hair Cells><Health><Hearing><Hearing Aids><Hearing Loss><Human><Hypoacuses><Hypoacusis><In Situ Hybridization><Infection><Injury><Internal Ear><International><Investments><Knock-out><Knockout><Label><Labyrinth><Larva><Libraries><Maps><Mechanoreceptors><Mediating><Medical Rehabilitation><Medication><Messenger RNA><Methods><Model System><Modern Man><Molecular><Monitor><Morphology><Mutagenesis><Mutagenesis Molecular Biology><Mutation><NGS Method><NGS system><Noise><Ortholog><Orthologous Gene><Otocadherin><Participant><Pathogenesis><Pathology><Patient Self-Report><Pattern><Persons><Pharmaceutical Preparations><Phenotype><Population><Presbyacusis><Presbycusis><QOL><Quality of life><Rehabilitation><Rehabilitation therapy><Reporter><Reporter Genes><Research Resources><Resources><Role><Self-Report><Startle Reaction><Swimming><System><Technology><Testing><Tissues><Transgenic Organisms><Variant><Variation><Visualization><Zebra Danio><Zebra Fish><Zebrafish><adulthood><age associated hearing loss><age induced hearing loss><age related decline in hearing><age related hearing deficits><age related hearing impairment><age related hearing loss><ages><aging associated hearing loss><aging induced hearing loss><aging related decline in hearing><aging related hearing deficits><aging related hearing impairment><aging related hearing loss><assistive hearing device><assistive listening device><behavior phenotype><behavioral phenotyping><candidate identification><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cost><developmental><disease model><disease phenotype><disorder model><drug induced hearing impairment><drug induced hearing loss><drug/agent><dysfunctional hearing><ear hair cell><exome sequencing><exome-seq><fertilizations><gene function><gene locus><genetic locus><genome mutation><genome wide analysis><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome wide studies><genome-wide analysis><genome-wide identification><genomewide association scan><genomewide association studies><genomewide association study><genomic location><genomic locus><hearing amplification><hearing assistance><hearing assistive device><hearing challenged><hearing defect><hearing deficient><hearing deficit><hearing device><hearing difficulty><hearing dysfunction><hearing impairment><hearing loss phenotype><in situ Hybridization Genetics><in situ Hybridization Staining Method><injuries><inner ear><inner ear development><insight><knockout gene><lateral line><loss of function><mRNA><mRNA Expression><model of animal><model organism><mutant><neuro-sensory><neuromast><neurosensory><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next gen sequencing><next generation sequencing><next generation therapeutics><nextgen sequencing><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ototoxic><ototoxicity><paralog><paralogous gene><rehab therapy><rehabilitative><rehabilitative therapy><screening><screenings><social role><spatiotemporal><startle response><therapeutic agent development><therapeutic development><transcriptional silencing><transgenic><whole genome association analysis><whole genome association studies><whole genome association study>