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Pathways towards regenerating the mammalian cochlea

哺乳动物耳蜗再生的途径

基本信息

批准号：
9514630
负责人：
Alan Gi-Lun Cheng
金额：
$ 41.39万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9514630
关键词：
Ablation Aftercare Agonist Aminoglycosides Animals Auditory Auditory Physiology Basilar Membrane Cell Count Cell Death Cell Differentiation process Cell Proliferation Cells Cochlea Cochlear Implants Competence Development Diphtheria Toxin Diuretics Embryo Flow Cytometry Fostering Genes Genetic Genetic Diseases Goals Hair Cells Hand Hearing Aids Histologic Human In Vitro Injections LGR5 gene Labyrinth Long-Term Effects Maintenance Mammals Maps Measures Mediator of activation protein Modeling Molecular Profiling Molecular Target Mouse Strains Mus Natural regeneration Nature Neonatal Noise Organ Organ of Corti Pathway interactions Pharmacology Play Process Proliferating Recovery Regimen Research Rest Role Sensorineural Hearing Loss Sensory Sensory Hair Signal Transduction Stem cells Supplementation Supporting Cell Techniques Therapeutic Tissues Transgenic Mice Transgenic Organisms WNT Signaling Pathway Work beta catenin cell injury diphtheria toxin receptor experimental study genetic signature hair cell regeneration hearing impairment in vivo insight ototoxin overexpression progenitor promoter public health relevance recombinase-mediated cassette exchange regenerative response restoration round window symptomatic improvement transcription factor

项目摘要

DESCRIPTION (provided by applicant): Cochlear degeneration is a major cause of sensorineural hearing loss (SNHL), and the lack of spontaneous regeneration contributes to the irreversible nature of SNHL. Prior studies have examined the utility of forced differentiation of hair cells in the degenerating cochlea, yet it remains unclear whether a restoration in cell number via cell proliferation can also aid cochlear regeneration. Recent work demonstrates that activation of canonical Wnt signaling via genetic or pharmacologic manipulation induces proliferation in the neonatal cochlea. Also, the competence to proliferate in response to Wnt signals is observed in both cochlear supporting cells and tympanic border cells below the basilar membrane. The goal of this proposal is to investigate whether supplementation of Wnt signals can stimulate proliferation and/or regeneration after hair cell degeneration in both the neonatal and mature cochleae. We will initiate degeneration with aminoglycoside application or via a transgenic strategy and concurrently fate-map supporting cells and tympanic border cells in vitro and in vivo. In parallel experiments using multiple transgenic mouse strains, we will study ablation targeting sensory hair cells or supporting cell subtypes. Wnt activation is achieved by using the Cre-Lox system in transgenic mice or local application of Wnt agonists and whether they will initiate proliferation of and regeneration by supporting cells and tympanic border cells are examined. The degree of damage and possible recovery in the cochlea are examined histologically and correlated with pre- and post-treatment auditory physiology in the whole animal. To gain an unbiased insight into the genetic signature of the damaged cochlea, supporting cells and tympanic border cells from undamaged and damaged cochlea are isolated via flow cytometry and subjected to gene array analyses. All transgenic mouse strains, pharmacologic agents, expertise to manipulate and examine the cochlea in vitro and in vivo, and techniques to isolate and enrich cochlear cells are at hand. Together, our research will determine 1) whether Wnt supplementation can help initiate cochlear regeneration and 2) additional targets to enhance this regenerative process in both the neonatal and mature cochleae.

描述（由申请人提供）：耳蜗变性是感音神经性听力损失（SNHL）的主要原因，缺乏自发再生导致SNHL的不可逆性。先前的研究已经检查了毛细胞在退化耳蜗中的强制分化的效用，但仍然不清楚通过细胞增殖恢复细胞数量是否也可以帮助耳蜗再生。最近的工作表明，通过遗传或药理学操作的经典Wnt信号的激活诱导新生儿耳蜗的增殖。此外，在耳蜗支持细胞和基底膜下的鼓膜边缘细胞中观察到响应于Wnt信号的增殖能力。本提案的目的是研究补充Wnt信号是否可以刺激新生儿和成熟耳蜗毛细胞变性后的增殖和/或再生。我们将通过应用氨基糖苷类药物或通过转基因策略启动变性，并同时在体外和体内对支持细胞和鼓膜边缘细胞进行命运图谱。在使用多个转基因小鼠品系的平行实验中，我们将研究靶向感觉毛细胞或支持细胞亚型的消融。通过在转基因小鼠中使用Cre-Lox系统或局部应用Wnt激动剂来实现Wnt活化，并检查它们是否会启动支持细胞和鼓膜边缘细胞的增殖和再生。对耳蜗的损伤程度和可能的恢复进行组织学检查，并与整个动物治疗前和治疗后的听觉生理学相关。为了获得对受损耳蜗的遗传特征的公正洞察，通过流式细胞术分离来自未受损和受损耳蜗的支持细胞和鼓膜边缘细胞，并进行基因阵列分析。所有转基因小鼠品系、药理学试剂、体外和体内操作和检查耳蜗的专业知识以及分离和富集耳蜗细胞的技术都在手边。总之，我们的研究将确定1）Wnt补充是否可以帮助启动耳蜗再生和2）其他目标，以增强新生儿和成熟耳蜗的再生过程。