Molecular Mechanisms of Tonotopy Development in the Brain Stem

脑干张力发育的分子机制

• 批准号: 9814554
• 负责人: Jason Tait Sanchez
• 金额: $ 33.09万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9814554
• 关键词: Address; Anatomy; Architecture; Auditory; Auditory Brainstem Responses; Auditory system; Biochemical; Biological; Biological Models; Biological Process; Birds; Brain Stem; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cell Therapy; Characteristics; Cochlea; Cochlear nucleus; Dendrites; Development; Disease; Down-Regulation; Electrophysiology (science); Embryo; Event; Foundations; Frequencies; Genetically Modified Animals; Genotype; Growth Factor; Hearing; Heterogeneity; In Vitro; Ion Channel; Labyrinth; Maintenance; Methods; Molecular; NGFR Protein; Nervous system structure; Neuraxis; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Neurotrophic Tyrosine Kinase Receptor Type 3; Pathway interactions; Pattern; Peripheral; Pharmacology; Phenotype; Play; Potassium; Property; Protein Tyrosine Kinase; Proteins; Receptor Signaling; Regulation; Research; Role; Sensory; Signal Transduction; Stem cells; Structure; Structure-Activity Relationship; Synapses; Testing; Therapeutic; Time; Tinnitus; Vertebrates; age related; auditory pathway; base; developmental neurobiology; experience; genetic manipulation; hearing impairment; in vivo; nerve supply; neural correlate; neuronal excitability; neurotrophic factor; new therapeutic target; receptor; receptor expression; relating to nervous system; sound; voltage

ABSRACT Normal nervous system maturation is dependent on neurotrophin signaling. Neurotrophins are proteins, and along with their signaling receptor pathways, help regulate the development, maintenance and function of vertebrate nervous systems, making it a dynamic factor that promotes biologically relevant tasks. Irregular neurotrophin signaling results in pathophysiological conditions throughout the peripheral and central nervous system. In the auditory periphery for example, this includes atypical arrangement of innervation patterns along the frequency gradient (i.e., tonotopic axis) of the inner ear and hearing loss. Beyond the auditory periphery of all vertebrates, however, the establishment of functional specialization in the central auditory pathway via neurotrophin signaling are lacking. Understanding gradients of neurotrophin signaling is a significant and timely problem in developmental neurobiology in general, and the avian auditory pathway proves to be a particularly advantageous model system for experimentally examining it. A better understanding of normal auditory circuit assembly – along with the unique functional properties of brainstem neurons – will provide a significant foundation for developing stem cell-based therapies for auditory-related disorders. Stem cell-derived auditory neurons will only prove useful, therapeutically, if they are able to re-create specialized functional properties that are characteristic of normal auditory circuit maturation. A careful characterization of neurotrophin signaling, the underlying molecular mechanism by which they operate, the role it plays in establishing normal auditory properties and the functional consequence of altering this biological process is necessary and appropriate. The research proposed here aims at addressing these issues by providing a comprehensive understanding of developmental properties associated with neurotrophin signaling and its role in establishing normal functional phenotypes along the tonotopic axis in the cochlear nucleus: a brainstem structure essential for the temporal processing of sound.

弃 正常神经系统的成熟取决于神经营养蛋白信号传导。神经营养蛋白是蛋白质， 以及它们的信号传导受体途径，有助于调节 脊椎动物神经系统，使其成为促进生物学相关任务的动态因素。不规律的 神经营养蛋白信号传导导致整个周围和中枢神经的病理生理状况 系统。例如，在听觉外围，这包括沿着神经支配模式的非典型布置 内耳和听力损失的频率梯度（即吨位轴）。超越听觉外围 但是，所有脊椎动物都通过在中央听觉途径中建立功能专业化 缺乏神经营养蛋白信号。了解神经营养蛋白信号的梯度是一个重要且及时的 一般而言，发育神经生物学的问题，鸟类的听觉途径被证明是一个特别的 有利的模型系统，用于实验检查。更好地了解正常听觉电路 组装 - 以及脑干神经元的独特功能特性 - 将提供重要的 开发基于干细胞的基于听觉相关疾病的疗法。干细胞衍生的听觉 如果神经元能够重新创建专业功能特性，则在治疗上只能证明有用 是正常听觉电路成熟的特征。仔细表征神经营养蛋白信号， 它们操作的基本分子机制，它在建立正常听觉方面所扮演的作用 属性和改变这种生物过程的功能后果是必要且适当的。 这里提出的研究旨在通过提供对这些问题来解决这些问题 与神经营养蛋白信号传导相关的发育特性及其在建立正常功能中的作用 人工耳蜗中沿体点轴的表型：临时必不可少的脑干结构 声音处理。