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Mouse vestibular regeneration and function

小鼠前庭再生和功能

基本信息

批准号：
10528434
负责人：
Alan Gi-Lun Cheng
金额：
$ 58.73万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10528434
关键词：
Ablation Acceleration Adult Age Algorithmic Analysis Animals Bioinformatics Candidate Disease Gene Cell Survival Cell physiology Cells Chickens Cochlea Data Data Analyses Dimensions Disease Dizziness Electric Capacitance Electrophysiology (science)Epithelium Equilibrium Evoked Potentials Functional disorder Gene Expression Genes Genetic Goals Hair Cells Histologic Histology Human Impairment In Situ Hybridization Label Legal patent Mammals Maps Measurement Measures Mechanoreceptor Cell Methods Morphology Mus Natural regeneration Organ Physiology Property Recovery Recovery of Function Research Role Sensory Sensory Hair Supporting Cell Synapses Techniques Technology Testing Time Transgenic Mice Transgenic Organisms Utricle structure Vertigo Vestibular Hair Cells Work Zebrafish candidate identification cell regeneration design effective therapy experimental study gain of function gene discovery gene expression database genetic signature hair cell regeneration improved in vivo insight loss of function mechanotransduction mouse model nerve supply novel organ regeneration overexpression partial recovery prevent regeneration model repaired response restoration single-cell RNA sequencing spatiotemporal stem cells transcription factor transcriptome vesicular release

项目摘要

Abstract: Sensory hair cells are required for balance function. Vestibular hair cell degeneration causes balance dysfunction/hypofunction manifested as dizziness and vertigo. While the mammalian cochlea lacks the ability to regenerate lost hair cells, a limited degree of spontaneous regeneration occurs in the utricle, a vestibular organ detecting linear acceleration. Recent studies using fate-mapping techniques have pinpointed supporting cells as precursors of regenerated hair cells. However, it is not clear whether regenerated hair cells are fully functional and if organ function recovers. In preliminary experiments we have characterized hair cell degeneration and regeneration in the mature mouse utricle and also a loss followed by recovery of vestibular evoked potentials (VsEP) in vivo. The first aim of this proposal is to determine if increasing hair cell regeneration improves the recovery of vestibular function. Specifically, regenerated hair cells labeled via fate-mapping are probed via histology and electrophysiology to assess bundle morphology, mechanosensitvity, basolateral currents, and synaptic properties including vesicle release. In parallel, VsEP responses are measured and compared to histologic and electrophysiological measures. Next, by overexpressing Atoh1 via a transgenic approach, we will study the histology and electrophysiology of Atoh1-overexpressing hair cells and also the overall VsEP responses. In the second aim, we will determine if Atoh1 deletion prevents hair cell regeneration and the recovery of VsEP responses. In parallel, fate-mapped, surviving hair cells will be examined for possible repair via histology and electrophysiology. To gain an unbiased insight into the genetic signature of hair cell progenitors and surviving hair cells, the third aim is designed to examine the damaged mature mouse utricle using single cell RNA sequencing technologies. Here the first goal is to discover the genetic landscape of hair cell progenitors and surviving hair cells in the damaged utricle. Secondly, we will examine the gene expression of the undamaged and damaged utricle after Atoh1 overexpression. Lastly, we will use bioinformatic approaches to delineate the trajectory of the spontaneous and Atoh1-enhaced supporting cell-hair cell transition and validate this histologically. In summary, we will apply state-of-the art technologies (vestibular physiology, hair cell physiology, single cell RNA-seq, bioinformatic strategies) to study vestibular hair cell regeneration in transgenic mouse models. We have assembled a team of experts who have worked together to collect promising preliminary data. At the end of this 5-year proposal, we will have 1) determined the relationship between hair cell regeneration and functional recovery and 2) revealed and temporally ordered novel genes during mammalian hair cell regeneration.

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