Publications by authors named "Linqing Zhang"

4 Publications

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Aldh inhibitor restores auditory function in a mouse model of human deafness.

PLoS Genet 2020 09 24;16(9):e1009040. Epub 2020 Sep 24.

Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanjing, China.

Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.
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http://dx.doi.org/10.1371/journal.pgen.1009040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553308PMC
September 2020

The Cation Channel TMEM63B Is an Osmosensor Required for Hearing.

Cell Rep 2020 05;31(5):107596

State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210032, China; Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China; Institute for Brain Sciences, Nanjing University, Nanjing 210032, China; Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210032, China. Electronic address:

Hypotonic stress causes the activation of swelling-activated nonselective cation channels (NSCCs), which leads to Ca-dependent regulatory volume decrease (RVD) and adaptive maintenance of the cell volume; however, the molecular identities of the osmosensitive NSCCs remain unclear. Here, we identified TMEM63B as an osmosensitive NSCC activated by hypotonic stress. TMEM63B is enriched in the inner ear sensory hair cells. Genetic deletion of TMEM63B results in necroptosis of outer hair cells (OHCs) and progressive hearing loss. Mechanistically, the TMEM63B channel mediates hypo-osmolarity-induced Ca influx, which activates Ca-dependent K channels required for the maintenance of OHC morphology. These findings demonstrate that TMEM63B is an osmosensor of the mammalian inner ear and the long-sought cation channel mediating Ca-dependent RVD.
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http://dx.doi.org/10.1016/j.celrep.2020.107596DOI Listing
May 2020

Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss.

J Clin Invest 2018 11 24;128(11):4938-4955. Epub 2018 Sep 24.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, China.

The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age-related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N-acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL.
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http://dx.doi.org/10.1172/JCI98058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205401PMC
November 2018

Loss of Myh14 Increases Susceptibility to Noise-Induced Hearing Loss in CBA/CaJ Mice.

Neural Plast 2016 22;2016:6720420. Epub 2016 Dec 22.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.

MYH14 is a member of the myosin family, which has been implicated in many motile processes such as ion-channel gating, organelle translocation, and the cytoskeleton rearrangement. Mutations in MYH14 lead to a DFNA4-type hearing impairment. Further evidence also shows that MYH14 is a candidate noise-induced hearing loss (NIHL) susceptible gene. However, the specific roles of MYH14 in auditory function and NIHL are not fully understood. In the present study, we used CRISPR/Cas9 technology to establish a Myh14 knockout mice line in CBA/CaJ background (now referred to as Myh14 mice) and clarify the role of MYH14 in the cochlea and NIHL. We found that Myh14 mice did not exhibit significant hearing loss until five months of age. In addition, Myh14 mice were more vulnerable to high intensity noise compared to control mice. More significant outer hair cell loss was observed in Myh14 mice than in wild type controls after acoustic trauma. Our findings suggest that Myh14 may play a beneficial role in the protection of the cochlea after acoustic overstimulation in CBA/CaJ mice.
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http://dx.doi.org/10.1155/2016/6720420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215640PMC
October 2017