# Molecular genetics of human age-related hearing loss

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $573,696

## Abstract

SUMMARY
The gradual loss of hearing is a common manifestation of aging, ultimately affecting communication and
leading to social exclusion and cognitive decline in the elderly population. Our long-term research goal is to
understand the elusive molecular pathways that are responsible for age-related hearing loss (ARHL) in
humans, to promote our understanding of, delay or prevent this condition. Our approach will be to mine and
dissect the list of 51 variants associated with human ARHL identified previously in two European populations,
which represent the largest genome-wide association study (GWAS) conducted to date. Our central hypothesis
is that the ARHL variants and associated genes can be grouped into functional networks. Here, we
propose to identify one of these functional networks starting from one variant that affects a gene for
which we have expertise, termed LOXHD1. LOXHD1 is expressed in hair cells, which are sensory cells of
the inner ear that are capable of transforming the force induced by sound into an electric current, a process
that is called mechanotransduction. We found that LOXHD1 is required for the mechanotransduction process
itself in mature hair cells. Because of the strong evolutionary conservation of the genes and mechanisms
involved in hearing among mammals, we hypothesize that the ARHL missense variant LOXHD1R1090Q can
be modeled in mice, to facilitate our understanding of the pathogenicity of its human orthologue.
In Specific Aim 1, we will determine the auditory phenotype of the aging mouse mutant Loxhd1R1064Q, which
mimics the human ARHL variant, and determine the localization of the LOXHD1 protein together with the
mechanotransduction channel in cochlear hair cells. By completing this aim, we expect to define the manner in
which LOXHD1R1090Q increases the susceptibility to ARHL in humans.
In Specific Aim 2, we will determine whether the ARHL LOXHD1 variant increases the susceptibility of the
animals to environmental insults, such as noise, and whether it accelerates the aging process in the ear. We
will determine the transcriptional program of hair cells during noise damage recovery in the presence of the
wild-type form or the ARHL variant.
In Specific Aim 3, we will use biochemistry to validate direct LOXHD1 putative interactors that also
correspond to ARHL genes. We will test if their localization is affected by LOXHD1 deficiency using antibodies
and tagged knock-in mice.
Overall, we expect to connect the first subset of human ARHL genes in a functional network. Our future work
will aim to define other subsets of genes to obtain the full picture of ARHL in European populations, and then
extend this approach to other populations.

## Key facts

- **NIH application ID:** 10637870
- **Project number:** 1R01AG081608-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Nicolas Grillet
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $573,696
- **Award type:** 1
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10637870

## Citation

> US National Institutes of Health, RePORTER application 10637870, Molecular genetics of human age-related hearing loss (1R01AG081608-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10637870. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*