Development studies of the inner ear

描述(由申请人提供)：我们研究的目标是了解在发育中的内耳中控制图案形成和细胞命运规范的时机和分子机制。内耳是脊椎动物独有的，内有听觉和平衡感的外周感受器。它由复杂的三维排列的组成细胞组成，其中包括神经元，组成不同感觉器官的受体，以及形成导管、小管和专门的分泌上皮的非感觉组织，这些组织是液体成分适当的动态平衡所需的。在人类和动物模型中，由于先天性缺陷或疾病而破坏内耳的精确形态可导致耳聋和/或平衡和平衡困难。我们努力了解导致内耳异常的根本缺陷，重点放在正常的发育过程和由特定基因缺陷引起的一连串事件上。在本研究中，我们重点研究Wnt信号转导。这个信号分子家族在进化过程中高度保守，与发育的许多方面有关，包括控制细胞增殖、细胞命运指定、形态发生运动、轴突引导和细胞沿体轴的方向。我们已经完成了28个Wnt相关基因在鸟类内耳发育过程中的空间和时间表达模式的全面图谱。我们的调查包括配体、受体和分泌性抑制物。这些数据导致了关于WNTS在耳朵发育的不同方面所起作用的几个假说。其具体目的是(1)探讨Wnt/2-catenin信号在耳蜗管中作为听觉和前庭(黄斑)感觉器官命运的开关的功能；(2)探讨Wnt信号在发育中的内耳中作为排斥性轴突引导线索的功能；(3)探讨Wnt相关分子在听觉感觉上皮中的径向梯度的功能。我们的发现可能为治疗策略提供基线数据，以指导干细胞沿着不同的发育命运修复或替换受损的内耳细胞。我们的研究项目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与人类先天性耳聋的遗传原因有关，希望这一知识可以应用于旨在再生或修复内耳细胞的治疗方法。

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.