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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：
10424508
负责人：
Jason Tait Sanchez
金额：
$ 32.64万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424508
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 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 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 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.

ABSRACT