[R01] Defining population-specific macrophage functions in noise-induced cochlear injury
Ente: National Institute on Deafness and Other Communication Disorders
Scadenza: 2031-06-30
Importo max: 657.396 EUR
Paese: US
Descrizione
Abstract:
Noise exposure causes permanent damage to the cochlea. A moderate level of noise causes
temporary threshold shifts (TTS), synapse loss, and subsequent repair, whereas a severe level of noise
causes permanent threshold shifts (PTS), and loss of hair cells and synapses. Noise also induces
inflammation in the cochlea by increasing the macrophage populations and upregulating inflammatory
genes among them. Broad ablation of macrophages prevents synapse repair after TTS, suggesting
that they mediate this recovery mechanism. However, several knowledge gaps exist and prevent us
from identifying precise therapeutic targets to treat noise-induced hearing loss: whether macrophages
are heterogenous and whether subsets of macrophages serve different functions in the cochlea
during homeostasis and post-damage are not known.
To bridge these gaps, we have in preliminary experiments found and characterized 3 subtypes
of macrophages with distinct transcriptomes and spatial distributions in the mature mouse cochlea. In
this proposal, we have designed two independent aims to interrogate the roles of these macrophage
subtypes in mice exposed to noise-induced TTS or PTS. In Aim 1, we will selectively ablate individual
macrophage subtypes and determine whether this approach confers protection or increases
susceptibility to TTS-induced synapse loss/recovery, spiral ganglion neuron loss, and wave 1 amplitude
decrease. Moreover, we will assess the spatiotemporal changes of macrophages, spiral ganglion
neurons, and other sensory and non-sensory cochlear cell types using single-cell RNA sequencing on
the cochlea after noise exposure. In Aim 2, we will ablate macrophage subtypes and assess their
effects on PTS-associated damage at both the histologic, physiologic, and transcriptomic levels.
In summary, we will apply state-of-the-art technologies (single-cell RNA-sequencing, novel
transgenic mouse models, bioinformatic strategies) to study the roles of macrophage subtypes in noise-
induced TTS and PTS. We have assembled a team of experts experienced in macrophage and
cochlear biology and physiology. At the end of this 5-year proposal, we will have 1) revealed whether
ablating macrophage subtypes affects the cochlea during homeostasis and post-noise, 2) revealed the
transcriptome of macrophage subtypes post-noise and identified putative therapeutic targets, 3)
revealed the transcriptomes of noise-susceptible sensory and non-sensory cell types post-noise and
after ablation of macrophage subtypes.
Istituzione: STANFORD UNIVERSITY
PI: Bahareh Ajami, Alan Gi-Lun Cheng
Progetto: 1R01DC024152-01
Settori: National Institute on Deafness and Other Communication Disorders
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