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Molecular Mechanisms of Tonotopy Development in the Brain Stem

脑干张力发育的分子机制

基本信息

批准号：
10622625
负责人：
Jason Tait Sanchez
金额：
$ 32.6万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622625
关键词：
Address Anatomy Architecture Auditory Auditory Brainstem Responses Auditory system Biochemical Biological Models Biological Process Birds Brain Stem Brain-Derived Neurotrophic Factor Cell Nucleus Central Nervous System 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 Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Neurotrophic Tyrosine Kinase Receptor Type 3 Pathway interactions Pattern Peripheral Nervous System Phenotype Play Potassium Presbycusis Property Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Research Role Sensory Shapes Signal Transduction Structure Structure-Activity Relationship Synapses Testing Therapeutic Time Tinnitus Vertebrates auditory pathway developmental neurobiology experience genetic manipulation hatching hearing impairment in vivo nerve supply nervous system development neural neural correlate neuronal excitability neurotrophic factor new therapeutic target pharmacologic receptor receptor expression sound stem cell therapy stem cells voltage

项目摘要

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.

摘要正常的神经系统成熟依赖于神经营养因子信号传导。神经营养因子是蛋白质，沿着它们的信号受体通路，帮助调节脊椎神经系统，使其成为促进生物相关任务的动态因素。不规则神经营养因子信号传导导致整个外周和中枢神经系统的病理生理状况系统例如，在听觉周边，这包括神经支配模式的非典型排列，沿着频率梯度（即，内耳的音调定位轴）和听力损失。在听觉外围之外，然而，所有的脊椎动物，通过中枢听觉通路建立功能特化，神经营养因子信号缺乏。了解神经营养因子信号的梯度是一个重要的和及时的一般来说，发育神经生物学中的问题，鸟类的听觉通路被证明是一个特别的问题。有利的模型系统进行实验检查。更好地了解正常的听觉回路组装-沿着脑干神经元独特的功能特性-将提供一个重要的该基金会致力于开发基于干细胞的治疗方法，用于治疗与癌症相关的疾病。干细胞源性听觉只有当神经元能够重新创造特殊的功能特性，是正常听觉回路成熟的特征神经营养因子信号的仔细表征，它们运作的潜在分子机制，它在建立正常的听觉系统中所起的作用，改变这种生物过程的性质和功能后果是必要和适当的。的这里提出的研究旨在通过提供对以下问题的全面了解来解决这些问题：与神经营养因子信号传导相关的发育特性及其在建立正常功能中的作用表型沿着耳蜗核的音调轴：一个对颞叶至关重要的脑干结构声音的处理。