Non-sensory cells as a potential source for signaling molecules in the cochlea

非感觉细胞作为耳蜗信号分子的潜在来源

• 批准号: 9127473
• 负责人: Lisa Goodrich
• 金额: $ 20.89万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127473
• 关键词: Alleles; Apple; Behavior; Brain; Cell physiology; Cells; Cochlea; Cochlear duct; Cues; Data; Development; Diagnosis; Duct (organ) structure; Embryo; Endolymph; Environment; Epithelium; Etiology; Family member; Floor; Flow Cytometry; Future; GJB2 gene; Gene Expression; Genes; Genetic; Hair Cells; Hearing; Human; Immunoglobulins; In Situ Hybridization; Knock-out; Learning; Left; Life; LoxP-flanked allele; Maintenance; Maps; Mediating; Methods; Minority; Modeling; Molecular; Molecular Genetics; Motion; Mus; Mutant Strains Mice; Mutation; NTN1 gene; Neurons; Organ of Corti; Pattern; Phenotype; Population; Positioning Attribute; Prevalence; Property; Proteins; Resources; Role; Sampling; Sensory; Signal Transduction; Signaling Molecule; Signaling Protein; Source; Staging; Stria Vascularis; Structure; Tamoxifen; Testing; Time; Tissue Harvesting; Tissues; Transgenic Mice; Travel; Vestibular membrane; behavior change; cell type; deafness; detector; differential expression; histological studies; improved; insight; molecular marker; mutant; neglect; neurotrophic factor; next generation sequencing; novel; novel marker; potassium ion; prevent; public health relevance; sodium ion; sound; spiral ganglion; tool; transmission process; vibration

 DESCRIPTION (provided by applicant): The sense of hearing depends on the perfect function of the cochlea, which is a highly organized structure made up of a wide array of cell types. Although hair cells are the primary detectors for sound, many other cells influence how wavelengths of sound travel through the cochlea and also establish the unique environment that is critical for hair cell activation and transmission of signals to spiral ganglion neurons. Hence, mutations that prevent the normal development or function of cells outside of the organ of Corti can also cause deafness, as exemplified by the prevalence of connexin-26 and pendrin mutations in the human population. Understanding how each of the specialized cell types in the cochlea develops to achieve its mature function will elucidate the diverse origins of deafness and improve methods of treatment. Among the least studied cells of the cochlea are the non-sensory cells that populate Reissner's membrane, the spiral limbus, and stria vascularis. To date, we know very little about how the early non-sensory epithelium is patterned to produce different types of cells, let alone how non-sensory cells might influence other cells in the cochlea. In fact, a number of secreted proteins, including neurotrophins, are produced by non-sensory cells, both during development and in the mature cochlea. We find that the secreted protein Netrin-1 (Ntn1) is produced by non-sensory cells in the roof of the developing cochlea. Surprisingly, extra neurons develop outside of the cochlear duct in mice completely lacking Ntn1 activity. Further, we discovered that non-sensory cells can be uniquely defined by expression of the immunoglobulin family member Lrig1. We therefore propose to use Lrig1 as a molecular handle to characterize the molecular and cellular properties of non-sensory cells and to investigate the role for non-sensory derived Ntn1 during cochlear development. These studies will allow us to explore the novel hypothesis that the non-sensory cochlea serves as a source for signaling molecules and will establish the resources needed to study and manipulate non-sensory cells and define their specific contribution to cochlear development, function, and the etiology of deafness.

 描述（由适用提供）：听力感取决于耳蜗的完美功能，这是由多种细胞类型组成的高度组织结构。尽管毛细胞是声音的主要探测器，但许多其他细胞会影响声音的波长如何穿过耳蜗，还建立了独特的环境，这对于毛细胞激活和信号传播至螺旋神经节神经元至关重要。因此， 防止皮尔蒂器官外部细胞正常发育或功能的突变也可能导致死亡性，这是人群中连接蛋白-26和pendrin突变的流行典型的例证。了解耳蜗中每种专门的细胞类型如何发展以实现其成熟功能，将阐明死亡的潜水员起源并改善治疗方法。在耳蜗的最不研究的细胞中，有填充了Reissner的膜，螺旋缘和Stria Vascularis的非感官细胞。迄今为止，我们对早期非感官上皮的图案如何产生不同类型的细胞知之甚少，更不用说非感官细胞如何影响耳蜗中的其他细胞了。实际上，在发育和成熟的耳蜗中，多种分泌的蛋白质，包括神经营养蛋白，都是由非敏感细胞产生的。我们发现，分泌的蛋白质Netrin-1（NTN1）是由发育中心的耳蜗屋顶中的非感官细胞产生的。出乎意料的是，在完全缺乏NTN1活性的小鼠中，在耳蜗管外发育额外的神经元。此外，我们发现可以通过免疫球蛋白家族成员LRIG1的表达来唯一定义非敏感性细胞。因此，我们建议将LRIG1用作分子手柄来表征非感官细胞的分子和细胞特性，并研究在人工耳蜗发育过程中非感官衍生的NTN1的作用。这些研究将使我们能够探索新的假设，即非敏感性耳蜗是信号分子的来源，并将建立研究和操纵非敏感细胞所需的资源，并定义其对人工耳蜗发育，功能和死亡学病因的特定贡献。