Development studies of the inner ear

内耳发育研究

• 批准号: 8231435
• 负责人: Donna M Fekete
• 金额: $ 36.81万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231435
• 关键词: Animal Model; Auditory; Axon; Basilar Papilla; Birds; Candidate Disease Gene; Cell Polarity; Cell Proliferation; Cells; Chickens; Cochlear duct; Coculture Techniques; Complex; Congenital Abnormality; Cues; Data; Defect; Development; Disease; Duct (organ) structure; Ear; Ectopic Expression; Embryo; Epithelium; Equilibrium; Esthesia; Event; Evolution; Family; Ganglia; Gene Delivery; Genes; Genetic; Goals; Hair; Hair Cells; Hearing; Homeostasis; Housing; Human; Knowledge; Laboratory Organism; Labyrinth; Ligands; Link; Liquid substance; Maps; Mediating; Methods; Molecular; Morphology; Movement; Mutation; Natural regeneration; Nervous system structure; Neurons; Organ; Otic Vesicle; Pathway interactions; Pattern; Peripheral; Primordium; Process; RNA Interference; Radial; Research; Role; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Source; Specific qualifier value; Stem cells; Surveys; Testing; Therapeutic; Time; Tissues; To specify; Transcript; Vertebrates; Virus; Width; axon guidance; cell fate specification; cell type; congenital deafness; deafness; gain of function; inhibitor/antagonist; knock-down; loss of function; macula; nerve supply; overexpression; programs; receptor; repaired; research study; transmission process

DESCRIPTION (provided by applicant): The goal of our research is to understand the timing and molecular mechanisms that control patterning and cell fate specification in the developing inner ear. The inner ear, unique to vertebrates, houses the peripheral receptors for the sensations of hearing and balance. It is composed of a complex three-dimensional arrangement of constituent cells which includes neurons, receptors grouped into distinct sensory organs, and non-sensory tissues that form the ducts, tubules and specialized secretory epithelia needed for proper homeostasis of the fluid components. In humans and animal models, disruption of the precise morphology of the inner ear due to congenital defects or disease can result in deafness and/or to difficulties with balance and equilibrium. Our efforts to understand the fundamental defects that result in inner ear abnormalities are focused on both the normal processes of development and on the cascade of events that can arise as a result of specific genetic defects. In this study, we focus on Wnt signaling. This family of signaling molecules has been highly conserved during evolution, and is linked to many aspects of development including control of cell proliferation, cell fate specification, morphogenetic movements, axon guidance and orientation of cells along the body axis. We have completed a comprehensive mapping of the spatial and temporal expression patterns of 28 Wnt-related genes during development of the avian inner ear. Our survey included ligands, receptors and secreted inhibitors. The data have led to several hypotheses about the role of Wnts in different aspects of ear development. The Specific Aims are (1) to explore the function of Wnt/2-catenin signaling as a switch between auditory and vestibular (macular) sensory organ fates in the cochlear duct; (2) to explore the function of Wnt signaling as a repulsive axon guidance cue in the developing inner ear; and (3) to explore the function of radial gradients of Wnt-related molecules across the auditory sensory epithelium. Our findings may provide baseline data for therapeutic strategies to direct stem cells along different developmental fates for repair or replacement of damaged inner ear cells. Our research program uses the chicken embryo to study the molecular pathways underlying development of the inner ear. The long-term goal of our research is to determine whether the molecules we identify may be linked to genetic causes of congenital deafness in humans, with the hope that this knowledge might be applied to therapeutic treatments aimed at the regeneration or repair of inner ear cells.

描述（由申请人提供）：我们研究的目标是了解控制发育中内耳模式和细胞命运规范的时间和分子机制。内耳是脊椎动物所特有的，它容纳了听觉和平衡感的外周感受器。它由组成细胞的复杂三维排列组成，所述组成细胞包括神经元、分组为不同感觉器官的受体以及形成流体组分的适当稳态所需的导管、小管和特化分泌上皮的非感觉组织。在人类和动物模型中，由于先天性缺陷或疾病导致的内耳精确形态的破坏可导致耳聋和/或平衡和平衡困难。我们努力了解导致内耳异常的基本缺陷，重点是正常的发育过程和特定遗传缺陷导致的级联事件。在这项研究中，我们专注于Wnt信号。该信号分子家族在进化过程中高度保守，并且与发育的许多方面相关，包括细胞增殖的控制、细胞命运的指定、形态发生运动、轴突引导和细胞沿体轴的定向沿着。我们已经完成了一个全面的映射的空间和时间的表达模式的28 Wnt相关基因在发展过程中的鸟类内耳。我们的调查包括配体，受体和分泌抑制剂。这些数据导致了关于Wnts在穗发育的不同方面的作用的几种假设。具体目的是（1）探索Wnt/2-连环蛋白信号传导作为耳蜗导管中听觉和前庭（黄斑）感觉器官命运之间的开关的功能;（2）探索Wnt信号传导作为发育中内耳中排斥性轴突引导线索的功能;以及（3）探索Wnt相关分子穿过听觉感觉上皮的径向梯度的功能。我们的发现可能为指导干细胞沿着不同的发育命运修复或替换受损内耳细胞的治疗策略提供基线数据。我们的研究计划使用鸡胚胎来研究内耳发育的分子途径。我们研究的长期目标是确定我们识别的分子是否可能与人类先天性耳聋的遗传原因有关，希望这些知识可以应用于旨在再生或修复内耳细胞的治疗性治疗。