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(申请人提供)：听力取决于耳蜗的完美功能，这是一个由多种细胞类型组成的高度组织化的结构。虽然毛细胞是声音的主要探测器，但许多其他细胞会影响不同波长的声音在耳蜗中的传播方式，并建立对毛细胞激活和向螺旋神经节神经元传输信号至关重要的独特环境。因此， 阻止Corti器官外细胞正常发育或功能的突变也可能导致耳聋，连接蛋白-26和Pendrin突变在人类群体中的流行就是例证。了解耳蜗中每种特殊细胞类型是如何发育以实现其成熟功能的，将有助于阐明耳聋的不同来源，并改进治疗方法。在研究最少的耳蜗细胞中，存在于Reissner膜、螺旋缘和血管纹的非感觉细胞。到目前为止，我们对早期的非感觉上皮是如何形成图案以产生不同类型的细胞知之甚少，更不用说非感觉细胞如何影响耳蜗中的其他细胞了。事实上，包括神经营养因子在内的许多分泌蛋白质都是由非感觉细胞产生的，无论是在发育过程中还是在成熟的耳蜗中。我们发现，分泌蛋白Netrin-1(Ntn1)是由发育中的耳蜗顶的非感觉细胞产生的。令人惊讶的是，在完全缺乏Ntn1活性的小鼠的耳蜗管外，会出现额外的神经元。此外，我们发现非感觉细胞可以通过免疫球蛋白家族成员Lrig1的表达来唯一地定义。因此，我们建议使用Lrig1作为分子手柄来表征非感觉细胞的分子和细胞特性，并研究非感觉来源的Ntn1在耳蜗发育中的作用。这些研究将使我们能够探索这一新的假设，即非感觉耳蜗作为信号分子的来源，并将建立研究和操纵非感觉细胞所需的资源，并确定它们对耳蜗发育、功能和耳聋病因的具体贡献。