Regeneration and reinnervation of mechanosensory hair cells

机械感觉毛细胞的再生和神经支配

• 批准号: 8196322
• 负责人: DAVID J KOZLOWSKI
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196322
• 关键词: Acoustic Trauma; Address; Affect; Animal Model; Auditory; Behavioral Assay; Biological; Blast Cell; Cell Count; Cell Proliferation; Cell physiology; Cells; Cellular biology; Chemical Exposure; Clinical; Cloning; Complex; Epithelium; Equilibrium; Financial compensation; Fishes; Functional disorder; Genes; Genetic; Genetic Screening; Genetic screening method; Goals; Growth; Hair Cells; Hearing; Hearing problem; Human; Inbreeding; Individual; Laboratories; Labyrinth; Life; Link; Mammals; Mediating; Messenger RNA; Mitotic; Modeling; Molecular Genetics; Natural regeneration; Neuraxis; Neurons; Organ; Pathway interactions; Phenotype; Population; Process; Regulation; Research; Role; Safety; Sensory; Sensory Hair; Services; Signal Pathway; Signal Transduction; Soldier; Source; Stem cells; Synapses; System; Testing; Vertebrates; Veterans; Visual; War; Zebrafish; abstracting; base; cell type; deafness; design; disability; gene discovery; genetic analysis; hair cell regeneration; hearing impairment; in vivo; in vivo regeneration; inhibitor/antagonist; insight; mutant; notch protein; novel; novel strategies; payment; public health relevance; regenerative; reinnervation; restoration; secretase

DESCRIPTION (provided by applicant): Project Summary/Abstract The inner ear is the primary sensory organ mediating hearing (auditory) and balance (vestibular) function in all vertebrates. Common to both the auditory and vestibular sensory epithelia are sensory hair cells, which are acutely sensitive to acoustic trauma. Loss of hair cells in the mammalian inner ear is irreversible and causes hearing impairment, deafness and balance dysfunction. In contrast to mammals, fish not only produce new hair cells throughout life but also have the innate capacity to regenerate functional hair cells. Using zebrafish as a regenerative animal model, this proposal is focused on the formation and regulation of long-lived hair cell precursors and the genetics of nascent hair cell reinnervation. The long-term goal of this proposal is to provide a molecular and genetic understanding of hair cell renewal in zebrafish and use this information to develop novel strategies that force hair cell regeneration and reinnervation in mammals. Specific Aim 1 is focused on the formation and regulation of postmitotic hair cell precursors that mediate non-mitotic hair cell regeneration in zebrafish. Using a newly identified strain of zebrafish, we show that Notch mRNA is expressed in the postembryonic sensory epithelium and that inhibitors of 3-secretase activity induce precocious hair cell formation in vivo. The goals of this Aim are to (a) determine the role of Notch signaling in regulating precursor differentiation, (b) determine the function of postmitotic precursors during growth and regeneration in the sensory epithelium, (c) identify the mitotic source of long-lived hair cell precursors, and (d) determine the genetic basis of non-mitotic hair cell regeneration in zebrafish. Specific Aim 2 will identify genes required for neuronal reinnervation of nascent sensory hair cells. Restoration of auditory function requires the inextricably linked processes of cell renewal and reconnection to the central nervous system. However, hair cell regeneration and reinnervation can be dissociated in vivo using molecular genetics and mutant identification in zebrafish. By exploiting simple visual and behavioral assays we will focus on (i) zebrafish mutants that do not regenerate hair cells and (ii) mutants that regenerate, but do not reinnervate nascent hair cells. Cloning of the affected loci in these mutants will identify novel genes, or known genes with novel functions, required for new hair cell formation and reestablishment of synaptic connectivity. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Hearing loss is the single most common individual disability in the veteran population. Nearly 60% of soldiers exposed to explosive blasts suffer permanent hearing loss and 28% of troops returning from a war zone have diminished hearing. Currently, more than 800,000 veterans are receiving disability compensation for service-connected hearing disorders, which is expected to grow by 18% a year with payments totaling $1.1 billion annually by 2011. Results of these proposed studies will provide new insight to the innate mechanisms of sensory hair cell regeneration and reinnervation. Since regeneration does not occur in mammals, this information is necessary to direct current research efforts and design novel strategies aimed toward ameliorating or reversing the effects of hearing loss in humans.

描述（由申请人提供）： 项目摘要/摘要内耳是所有脊椎动物调节听觉（听觉）和平衡（前庭）功能的主要感觉器官。听觉和前庭感觉上皮的共同点是感觉毛细胞，它们对声损伤非常敏感。哺乳动物内耳毛细胞的损失是不可逆的，会导致听力障碍、耳聋和平衡功能障碍。与哺乳动物相比，鱼类不仅在一生中产生新的毛细胞，而且具有再生功能性毛细胞的先天能力。该提案使用斑马鱼作为再生动物模型，重点研究长寿毛细胞前体的形成和调节以及新生毛细胞神经支配的遗传学。该提案的长期目标是提供对斑马鱼毛细胞更新的分子和遗传学理解，并利用这些信息来开发迫使哺乳动物毛细胞再生和重新神经支配的新策略。具体目标 1 侧重于介导斑马鱼非有丝分裂毛细胞再生的有丝分裂后毛细胞前体的形成和调节。使用新鉴定的斑马鱼品系，我们发现 Notch mRNA 在胚胎后感觉上皮中表达，并且 3-分泌酶活性抑制剂可诱导体内毛细胞早熟形成。该目标的目标是（a）确定Notch信号在调节前体分化中的作用，（b）确定有丝分裂后前体在感觉上皮生长和再生过程中的功能，（c）确定长寿命的有丝分裂来源毛细胞前体，以及（d）确定斑马鱼非有丝分裂毛细胞再生的遗传基础。具体目标 2 将鉴定新生感觉毛细胞神经元重新神经支配所需的基因。听觉功能的恢复需要细胞更新和与中枢神经系统重新连接的紧密联系的过程。然而，利用斑马鱼的分子遗传学和突变体鉴定，可以在体内分离毛细胞再生和神经支配。通过利用简单的视觉和行为分析，我们将重点关注（i）不再生毛细胞的斑马鱼突变体和（ii）可再生但不重新支配新生毛细胞的突变体。这些突变体中受影响基因座的克隆将鉴定新的基因或具有新功能的已知基因，这是新毛细胞形成和突触连接重建所需的。 公共卫生相关性： 7. 项目叙述 听力损失是退伍军人中最常见的个人残疾。近 60% 遭受爆炸袭击的士兵患有永久性听力损失，28% 从战区返回的士兵听力下降。目前，超过 800,000 名退伍军人正在因服役相关的听力障碍而领取伤残补偿，预计到 2011 年，这一数字将以每年 18% 的速度增长，每年支付总额将达到 11 亿美元。这些拟议研究的结果将为了解听力障碍的先天机制提供新的见解。感觉毛细胞再生和神经支配。由于哺乳动物不会发生再生，因此这些信息对于指导当前的研究工作和设计旨在改善或逆转人类听力损失影响的新策略是必要的。