Development of Afferent and Efferent Innervation in the Inner Ear

内耳传入和传出神经支配的发育

• 批准号: 10040190
• 负责人: Jemma Louise Webber
• 金额: $ 11.58万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-06 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10040190
• 关键词: Address; Afferent Neurons; Area; Auditory; Auditory Perception; Auditory system; Award; Back; Biological Models; Brain; Brain Stem; Caenorhabditis elegans; Candidate Disease Gene; Cells; Cochlea; Cochlear duct; Communities; Defect; Development; Disease; Drosophila genus; Ear; Efferent Neurons; Embryo; Epithelial; Epithelium; Feedback; Fiber; Funding; Future; Genes; Goals; Grant; Hair Cells; Hair Removal; Hearing; Inner Hair Cells; Institution; Journals; Knowledge; Labyrinth; Lateral; Lead; Location; Medial; Mentors; Modeling; Molecular; Mus; Nerve; Neuraxis; Neurobiology; Neurologic; Neurons; Organ of Corti; Outer Hair Cells; Pain; Pathway interactions; Pattern; Pharmacotherapy; Phenotype; Play; Positioning Attribute; Prevention strategy; Publishing; Quality of life; Receptor Cell; Reporting; Research; Research Personnel; Resources; Role; Sensorineural Hearing Loss; Sensory; Sensory Receptors; Synapses; Technical Expertise; Testing; Transcriptional Regulation; Universities; Vestibular ganglion; Viral Vector; Work; Zinc Fingers; axonal pathfinding; career; cell transformation; cell type; deafness; hearing impairment; hearing loss treatment; improved; mouse genetics; mouse model; mutant; nerve supply; neural circuit; neuronal circuitry; normal hearing; novel; regenerative therapy; ribbon synapse; sound; spiral ganglion; success; tenure track; transcription factor; transcriptome sequencing; treatment strategy

Project Summary/Abstract The neuronal pathways that connect the ear to the brain are not well understood. For decades, work has focused on understanding how damage to hair cells (the sensory receptors in the inner ear) impacts hearing. We now know that the neuronal circuits that transmit auditory information detected by the hair cells are even more vulnerable to damage. Further, this damage is permanent and has lasting impact on quality of life. Deepening our understanding of how neuronal circuits are established and maintained in normal hearing will be a critical to better understand disease and improve prevention and treatment strategies. The perception of sound begins in the cochlea, where hair cells detect and transmit auditory input to the brainstem via afferent neurons. Efferent neurons provide feedback control allowing tuning of this input. These neurons are born early in development and following differentiation send projections to the cochlea sensory epithelium where they make highly specific connections with two types of hair cell: the inner and outer hair cells (IHCs and OHCs). How these projections track to the appropriate location within the cochlea (either along the cochlear duct, or between inner and outer compartments) is not well understood. The goal of this proposal is to obtain a comprehensive picture of how afferent and efferent innervation patterns are set up in the organ of Corti. Using a recently described Insm1 mouse model, in which IHCs are intermingled with OHCs in the outer compartment (oc-IHCs), I will test the hypothesis that there is a hierarchical model of innervation such that hair cell type dictates afferent innervation which in turn determines the type of efferent innervation received (aim 1). Additionally, using a combination of mouse genetics and cochlear explant cultures combined with viral vectors, I will test novel candidate genes for roles in axonal pathfinding and branching in the cochlea (aim 2 and alternative aim 2/future goals). I believe these aims will materially advance our understanding of the neuronal circuits within the ear and ultimately lead to the development new and improved treatments for hearing loss. My long term career goal is to establish myself as an independent investigator at a top research institution. Given I have recently moved research field (and model system) from transcriptional regulation to neurobiology, this award would allow me to a) gain depth and breadth of knowledge, and technical expertise in the auditory field b) publish my work in reputable journals and c) develop an independent project that can be used to obtain my own independent funding and tenure track position. With the combination of this grant, the expert guidance by my mentoring team and the expertise and resources available to me through the broader auditory community established here at Northwestern University means that I will have every chance of success.

项目概要/摘要 连接耳朵和大脑的神经通路尚不清楚。几十年来，工作 专注于了解毛细胞（内耳中的感觉受体）的损伤如何影响听力。 我们现在知道，传递毛细胞检测到的听觉信息的神经元回路是均匀的。 更容易受到损坏。此外，这种损害是永久性的，并对生活质量产生持久影响。 加深我们对正常听力中神经回路如何建立和维持的理解将 对于更好地了解疾病和改进预防和治疗策略至关重要。 对声音的感知始于耳蜗，毛细胞检测并将听觉输入传输到耳蜗 脑干通过传入神经元。传出神经元提供反馈控制，允许调整该输入。这些 神经元在发育早期诞生，分化后将投射发送到耳蜗感觉 上皮细胞与两种类型的毛细胞建立高度特异性的连接：内毛和外毛 细胞（IHC 和 OHC）。这些投影如何追踪到耳蜗内的适当位置（沿着 耳蜗管，或内室和外室之间）尚不清楚。 该提案的目标是全面了解传入和传出神经支配模式 是建立在柯蒂氏管内的。使用最近描述的 Insm1 小鼠模型，其中 IHC 与外室中的 OHC（oc-IHC）混合，我将检验以下假设： 神经支配的分层模型，使得毛细胞类型决定传入神经支配，进而决定 接受的传出神经支配的类型（目标 1）。此外，结合小鼠遗传学和 耳蜗外植体培养与病毒载体相结合，我将测试新的候选基因在轴突中的作用 耳蜗中的寻路和分支（目标 2 和替代目标 2/未来目标）。我相信这些目标将会 实质性地增进了我们对耳内神经元回路的理解，并最终导致 开发新的和改进的听力损失治疗方法。 我的长期职业目标是成为顶尖研究机构的独立研究员。 鉴于我最近将研究领域（和模型系统）从转录调控转移到神经生物学， 这个奖项将使我能够 a) 获得深度和广度的知识以及听觉方面的技术专长 b) 在知名期刊上发表我的作品 c) 开发一个独立项目，可用于获得 我自己的独立资助和终身教职职位。结合本次资助，专家指导 通过我的指导团队以及通过更广泛的听觉向我提供的专业知识和资源 在西北大学建立的社区意味着我将有一切成功的机会。