Molecular embryology of the mammalian inner ear

哺乳动物内耳的分子胚胎学

基本信息

批准号：
9205223
负责人：
JOHN Vincent BRIGANDE
金额：
$ 38.08万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9205223
关键词：
Address Alkaline Phosphatase Anatomy Anterior Auditory Base Sequence Behavior Biological Models Birds Cell Differentiation process Cells Chimeric Proteins Complex DNA Sequence Alteration Data Data Set Daughter Development Disease Duct (organ) structure Ectoderm Embryo Embryology Endolymphatic duct Enterobacteria phage P1 Cre recombinase Epithelial Epithelial Cells Epithelium Equilibrium Evaluation Fiber Optics Functional disorder Funding Gene Expression Genes Genetic Genetic Recombination Goals Hair Cells Hearing Human Image-Guided Surgery Individual Instruction Intervention Knowledge Label Laboratories Labyrinth Lateral Libraries Locales Location LoxP-flanked allele Maps Mediating Membrane Microinjections Mitosis Molecular Morphogenesis Mus Neural Crest Neural tube Neuroepithelial Neuroepithelial Cells Neurons Oligonucleotides Organ Otic Vesicle Output Pattern Pattern Formation Population Recording of previous events Regulation Reporter Retroviridae Sensory Signal Transduction Specific qualifier value Stem cells Structure Supporting Cell Techniques Testing Tissues Ultrasonography Vestibular Hair Cells Virus Virus Integration Virus Receptors base cell fate specification daughter cell design env Gene Products experimental study genetic manipulation in utero in vivo inner ear development mammalian embryology nerve stem cell novel otoconia placodal ectoderm precursor cell progenitor public health relevance relating to nervous system restoration spiral ganglion

项目摘要

DESCRIPTION (provided by applicant): The long term goal of our laboratory is to define gene- and cell-based strategies that restore hearing and balance in the dysfunctional inner ear. The short term goals are to advance our understanding of morphogenesis, pattern formation, and cell fate specification in the mouse inner ear. We use the mouse as a model system because an ever-expanding array of natural and induced genetic mutations exist that serve as accurate paradigms for human inner ear dysfunction. Our overarching technical approach relies on experimental embryology, a palette of surgical, imaging, microinjection and molecular techniques that permit access to the developing mouse inner ear in utero and enable genetic manipulation of precursor cells that give rise to the auditory and vestibular sensory structures. I this proposal, we aim: 1) to fate map the mouse otic vesicle in vivo~ 2) to define the types of cel fate choices otic precursors make and the timing of those choices~ and 3) to define the clonal contributions of neuroepithelial progenitors to the differentiated inner ear. A fate map describes what distinct populations of cells become as the inner ear matures. Developmental biologists use fate maps to understand how progenitor gene expression in a developing tissue or organ drives maturation and results in the acquisition of form and function. Intersection of indelibly labeled precursors with known domains of gene expression can teach us the molecular signals required to pattern sensory organs and specify cell fate. Lineage analysis, on the other hand, identifies the differentiated cells an individual otic precursor makes and reveals their location i the mature sensory organ. Clonal relationships will teach us if genetically defined pools of precursors are programmed early on in development to give rise to gross anatomical structures in the inner ear and to the sensory patches. The output of fate mapping and lineage analysis is a deeper understanding of the genetic regulation of progenitor cell identity and behavior. And that regulation promises to be far more complex that originally envisioned. Recent genetic fate mapping data show that neuroepithelial progenitor cells from the neural tube and likely the neural crest contribute precursor cells to the otic epithelium that generate sensory and nonsensory cells upon differentiation. These novel data firmly challenge the precept that the inner ear develops exclusively from placodal ectoderm and imply that neural ectoderm may uniquely participate in patterning and cell fate specification. Clonal analysis of these geneticall separable neuroepithelial precursor populations will advance our core knowledge about the embryonic origins of the mouse inner ear. A more complete understanding of the fate, lineage, and behavior of inner ear progenitor cells will inform the design of gene- and cell-based strategies aimed at the restoration of hearing and balance.

描述（由申请人提供）：我们实验室的长期目标是定义基于基因和细胞的策略，以恢复功能失调内耳的听力和平衡。短期目标是提高我们对小鼠内耳中形态发生，模式形成和细胞命运规范的理解。我们将小鼠用作模型系统，因为存在不断扩展的天然和诱导基因突变阵列，它们是人类内耳功能障碍的准确范式。我们的总体技术方法依赖于实验性胚胎学，这是一种手术，成像，显微注射和分子技术的调色板，允许进入子宫内发育中的小鼠内耳，并启用对前体细胞的基因操纵，从而引起听觉和前庭的感觉结构。我的建议，我们的目的是：1）在体内绘制小鼠耳囊的命运，以定义Cel命运选择的类型，以及这些选择的时间和这些选择的时间〜和3）定义神经上皮祖细胞对差异化的内耳的克隆贡献。命运图描述了随着内耳成熟的变化，细胞的不同种群。发育生物学家使用命运图来了解发展组织或器官中祖细胞基因的表达如何驱动成熟并导致形式和功能的获取。不可磨灭的前体与已知的基因表达结构域的交点可以教给我们模拟感觉器官并指定细胞命运所需的分子信号。另一方面，谱系分析识别了单个耳片前体的分化细胞，并揭示了其位置I成熟的感觉器官。克隆关系将教会我们，如果在开发的早期进行了遗传定义的前体池，以产生内耳内部和感觉斑块的粗糙解剖结构。命运映射和血统分析的输出是对祖细胞身份和行为的遗传调节的更深入的理解。这种法规有望将最初设想的更为复杂。最近的遗传命运映射数据表明，来自神经管的神经上皮祖细胞，可能会导致前体细胞对眼皮上皮细胞，从而在分化后产生感觉和非感官细胞。这些新的数据牢固地挑战了内耳专门从placodal外胚层发展的戒律，这意味着神经外胚层可能唯一地参与图案和细胞命运规范。对这些遗传可分离神经上皮前体种群的克隆分析将提高我们对小鼠内耳胚胎起源的核心知识。对内耳祖细胞的命运，谱系和行为的更全面了解将为旨在恢复听力和平衡的基于基因和细胞的策略的设计。