The adult mouse cochlea after sensory hair cell loss and experiments towards inner ear regeneration

• Applicant: Dr. Ayse Maraslioglu-Sperber
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Otolaryngology, Phoniatrics and Audiology ; Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504694433

Lost avian auditory hair cells (HCs) regenerate after loud noise exposure or aminoglycoside ototoxicity. The source of the new HCs is mitotically active or directly transdifferentiating supporting cells (SC) of the avian basilar papilla. In contrast, SCs of the mature mammalian organ of Corti lack the ability to replace lost HCs. Every year, HC loss through genetic disorders, aging, noise exposure, or medications causes hearing loss in millions of people worldwide. Understanding the regenerative mechanisms in birds and translating these findings towards mammals is a valuable strategy for finding therapies against hearing loss in humans. Targeted therapeutics require molecular and cytomorphological understanding of the inner ear sensory epithelium during and after HC loss. Prof. Stefan Heller’s team at the Stanford University has developed a robust avian HC loss model and explored the dynamic expression profiles of regenerating SCs to identify signaling pathways that control S-phase entry in avian SCs. The ability to manipulate its genome made the mouse the foremost mammalian model organism for studying human diseases. I will use the mouse as a model organism to understand cellular interactions between dying HCs and surviving SCs, and to compare the differences between chicken SCs that enter a regenerative program and the quiescent mouse SCs. To do so, I will first establish a reliable murine HC loss model equivalent to the chicken model. My aim is to establish the correct dose of the ototoxic aminoglycoside sisomicin to elicit substantial loss of cochlear HCs, while SCs remain unaffected. I will characterize the SCs histologically during and after HC loss, which is fundamental for the subsequent steps, as those results will provide cytomorphological knowledge of the surviving SCs that restructure the damaged organ of Corti. I will further transcriptomically profile SCs during and four weeks after HC loss to identify highly active promoters in the surviving SCs, besides inventorying the gene expression in the damaged adult organ of Corti. The results from the histological and transcriptomic analysis will guide my strategy to establish robust infection and Adeno-associated virus-driven gene expression in SCs after HC loss. Finally, I will combine the HC loss model and the newly established gene delivery method with existing knowledge about the triggers of proliferative HC regeneration in chickens to screen for genes and drugs that trigger S-phase entry of surviving SCs in the adult mouse cochlea. In summary, I will systematically evaluate the cell identity, gene expression profile, and infectability of the surviving SCs in the adult mouse cochlea after HC loss. Existing knowledge of the mechanisms that drive HC regeneration in birds, and the transcriptomic identity of the non-regenerating murine SCs will offer new strategies to trigger SC-mediated HC regeneration in the adult murine cochlea, which is the overarching goal of this research proposal.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Stefan Heller, Ph.D.