Hearing loss affects roughly 1.5 billion people worldwide, and a specific mutation in a receptor for a lipid signalling molecule called S1P causes early-onset, progressive hearing loss in mice and humans. The problem is that current treatments—hearing aids and cochlear implants—only manage symptoms, not the underlying biology. This project targets a gap: we know immune cells are involved in cochlear damage, but the molecular triggers are poorly understood. The researchers will map how immune activation unfolds in the inner ear as hearing declines, use genetic tools to pinpoint which cell types drive inflammation, and test drugs that modulate the immune response. If successful, this work could identify a therapeutic window—a period before permanent hair cell death—where an immunomodulatory drug might slow or reverse hearing loss. That would shift treatment from assistive devices to disease-modifying therapy. This is fundamental science: understanding how a single receptor mutation sets off a chain of inflammation and tissue damage. Similar mechanistic insights into immune signalling have led to treatments for autoimmune diseases, so a clearer picture of cochlear immunity could eventually yield drugs that preserve hearing.
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Hearing loss (HL) affects ~1.5 billion worldwide, has profound psychosocial and economic consequences, and is a significant predictor of dementia. Prevalence is projected at 2.5 billion by 2050; however, treatment is limited assistive devices that partially alleviate symptoms without addressing pathophysiology. Therefore, an etiological understanding of HL will inform the development of disease-modifying therapeutics. Leukocytes are implicated in cochlear homeostasis and dysfunction, but the underlying molecular mechanisms are underexplored. Sphingosine-1-phosphate (S1P) is a lipid mediator of vascular tone, barrier function, and immune cell trafficking, and mutations in S1P pathway components cause HL in mice and humans. The ‘stonedeaf’ allele of S1P receptor-2 (S1pr2) results in a T289R substitution within the transmembrane zone. Homozygous mice exhibit early-onset and progressive HL, endocochlear potential decline, stria vascularis defects, and subsequent hair cell degeneration. Here, S1pr2-related inflammation may trigger early cochlear pathology, offering a therapeutic window before irreversible hair cell degeneration. This project aims to define potential immune mechanisms underlying S1pr2-related HL and identify therapeutic targets. Objectives include: i) profiling cochlear immune activation throughout disease progression; ii) temporal and cell-type-specific S1pr2 recombination strategies to identify drivers of cochlear inflammation; and iii) evaluating immunomodulatory compounds predicted to prevent, slow, or reverse cochlear pathology and HL.
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