https://reporter.nih.gov/search/ddHB5clCeU2ogGyLiewqlw/project-details/10771262
Projects
Contribution of Macrophages and Fractalkine Towards Degeneration and Repair of Cochlear Synapses
Parent Project Number
1P20GM139762-01
Sub-Project ID
5859
Contact PI/Project Leader
KAUR, TEJBEER
Awardee Organization
CREIGHTON UNIVERSITY
Abstract
Project Summary/Abstract: Noise trauma can primarily damage the synaptic connections between the inner hair cells and the peripheral axons of the spiral ganglion neurons. Noise-induced synaptopathy is attributed to glutamate excitotoxicity and leads to gradual axonal degeneration and ultimately death of the spiral ganglion neurons. The consequences of loss of synapses and neurons include auditory perceptual dysfunctions leading to difficulty in speech recognition and listening in noisy environments. This type of auditory dysfunction is known as “hidden hearing loss” because it is not readily diagnosed through standard hearing tests. Moreover, absence of spiral ganglion neurons limits the performance of primary therapies for hearing loss such as cochlear implants and future hair cell regeneration strategies. Currently, there are no approved drugs that promote neuron survival or elicit regeneration of lost auditory nerves and replenish their synaptic connections with surviving hair cells. Therefore, it is of great interest to understand the mechanisms for synaptic and neuron degeneration and regeneration for the development of better ototherapeutics.
We recently demonstrated that synaptopathic noise trauma is sufficient to recruit macrophages (innate-immune cells) towards the damaged inner hair cell-synaptic region. While the damaged synapses can undergo spontaneous repair however, disruption of fractalkine signaling (by genetic deletion of fractalkine (FKN) receptor CX3CR1 on macrophages) impairs such spontaneous synaptic repair and increases spiral ganglion neuron loss after trauma. These data imply that intact fractalkine signaling is necessary for synaptic repair and neuron survival in the damaged cochlea.
Here, we propose to investigate the effect of activation of fractalkine signaling on prevention and repair of loss of synapses and neuron survival following cochlear trauma.
- Aim 1 will determine whether FKN treatment repairs damaged synapses after noise trauma or excitotoxic insult in mammalian mouse cochlea. Specifically, FKN peptide will be injected either (transtympanically) after synaptopathic noise trauma in vivo or after glutamate- induced excitotoxicity in cochlear explants. The precise contribution of FKN membrane or soluble isoforms towards synaptic repair will be examined.
- Aim 2 will determine whether FKN treatment reduces degeneration of synapses following noise trauma or glutamate excitotoxicity. We will treat with FKN membrane or soluble isoforms prior to glutamate treatment in ex vivo cochlear explants or prior to noise trauma in vivo (transtympanically).
- In Aim 3, we will eliminate cochlear macrophages and examine the influence of this intervention on the degree of synaptic degeneration and repair after synaptopathic noise trauma. For each aim, auditory function along with morphometric analyses of hair cell, macrophage, synapse and spiral ganglion neuron counts will be performed.
Together, the study design will aid in investigating the effect of macrophages and fractalkine treatment on cochlear synapse degeneration and repair and hearing restoration and may lead to identification of novel fractalkine-based therapeutics for “hidden-hearing loss”.
Project Funding for FY 2021
$288,481
The effects of cochlear pericytes and pericyte-related vascular pathology on hearing function
The Role of Notch Signaling in the Maintenance and Function of Cochlear Sensory Cells
Project Number: 1F31DC018198-01
Contact PI / Project Leader: GILELS, FELICIA AILEEN
Title: THE ROLE OF NOTCH SIGNALING IN THE MAINTENANCE AND FUNCTION OF COCHLEAR SENSORY CELLS
Awardee Organization: UNIVERSITY OF ROCHESTER
Abstract Text:
The six sensory organs of the mammalian inner ear function to mediate hearing and balance. Mechanosensory hair cells, supporting cells, and spiral ganglion neurons are three essential cell types that comprise the inner ear sensory regions. Hearing loss is commonly caused by damage to these essential cell types which, in mammals, lack the capacity to regenerate. Thus, identifying signaling pathways that are involved in the development and maintenance of these cell types is of great importance. Notch has been shown to play two essential roles in embryonic inner ear sensory development: 1) establishes the prosensory progenitors that give rise to hair cells and supporting cells, and 2) mediates which cell fate is adopted by the sensory precursor, either hair cell or supporting cell. Despite these important early roles, there is a limited understanding of the function of Notch signaling postnatally. The Notch ligand Jagged1 (JAG1) has dynamic expression throughout inner ear development, and is the only reported Notch ligand maintained into adulthood where it is expressed in supporting cells. Here, to understand the role of JAG1-Notch signaling in the postnatal inner ear we utilize a Cre/loxP recombination system to conditionally delete either JAG1 or Notch receptors in supporting cells at postnatal day (P)0/P1 and assess for effects on hearing and cochlear morphology. Preliminary results indicate that JAG1 signaling is required postnatally for normal hearing function, as Sox2-Jag1cko mice display a specific form of hearing loss termed auditory neuropathy, that specifically affects the inner hair cell pathway. In Aim 1, we will determine how JAG1 signaling functions in maturation and/or maintenance of the postnatal cochlea and test our hypothesis that postnatal JAG1 signaling influences stereocilia morphogenesis and/or maintenance. In Aim 2, we will identify the Notch receptor mediating the effects of JAG1 in the postnatal cochlea and test the hypothesis that JAG1 signals through the Notch1 and/or Notch2 receptor(s) in postnatal cochlear supporting cells. Our preliminary data suggests Notch1 may be the predominant JAG1 receptor as Sox2-Notch1cko mice show profound deafness at 6-weeks of age. These studies will elucidate novel functions for JAG1-Notch signaling in hearing maturation and/or maintenance in the postnatal cochlea.
Public Health Relevance Statement:
Hearing and vestibular disorders commonly occur from loss or damage to critical cell types (mechanosensitive hair cells, supporting cells, and spiral ganglion neurons), which in mature mammals are not replaced. Potential therapeutic strategies to treat these disorders may involve cell replacement or regenerative therapies; however, a prerequisite for this approach is the identification of signaling pathways involved in the development and maintenance of these cell types. Elucidating novel functions for JAG1-Notch signaling, previously implicated in establishing embryonic prosensory progenitors and mediating progenitor cell fate adaptation, will create insights into the molecular mechanisms of hearing maturation/maintenance in the postnatal cochlea; this knowledge will provide a platform for future therapies designed to restore inner ear function.
Source:
https://projectreporter.nih.gov/project_info_description.cfm?aid=9833706