Role of endothelin signaling in the development of intermediate cells in the stria vascularis

摘要 血管纹是哺乳动物耳蜗的一种特殊的上皮性结构，它产生内淋巴，内淋巴是一种富含钾的液体，负责耳蜗腔的正电耳内电位。 这种正的胞外电位是感觉神经元正确信号转导的主要驱动力。 耳朵，因此是正常的听力。血管纹是听觉器官的“电池”。它被本地化在 耳蜗侧壁，由多层高度血管化的上皮组成。它由以下部分组成 具有不同胚胎起源的三种主要细胞类型：来源于耳廓上皮的边缘细胞， 中间细胞是从迁移的神经脊细胞衍生而来的特化的黑素细胞样细胞，以及 起源于耳间充质的基底细胞。中胚层来源的血管散布在 这些细胞遍布整个纹状体。血管纹发育缺陷是许多 人类可遗传耳聋综合征，包括先天性巨结肠症和Waardenburg，Jervell和 兰格-尼尔森综合征、巴特综合征和芝麻综合征。在过去的十年里，人们做出了巨大的努力来 了解哺乳动物耳蜗中感觉细胞的发育，目的是应用它们的 再生疗法的发展原则。相比之下，人们对这种发育过程知之甚少。 血管纹的潜力，甚至是由于衰老而导致的工业退化的机制。我们的长期合作 目标是了解管理Stria发展的原则，并将它们应用于设计 先天性工业畸形或工业老年性耳聋的修复和再生治疗神经脊细胞是具有多潜能的迁移性胚胎细胞的瞬时群体。在内耳，神经脊细胞产生第七神经节的神经胶质细胞和血管纹的中间细胞。中间细胞是正常的ALT功能所必需的，尽管它们似乎与黑素母细胞有共同的起源，但黑色素本身并不是听力所必需的。影响神经脊发育或迁移的突变通常会导致包括耳聋在内的综合征。人类内皮素受体B基因(EDNRB)突变导致先天性巨结肠症。该综合征的感觉神经性耳聋是血管纹萎缩，缺乏中间细胞的结果。本研究的目的是研究神经沟来源的中间细胞在血管纹中的迁移、分化和与其他细胞的相互作用，以及内皮素信号在这些过程中所起的作用。

ABSTRACT The stria vascularis is a specialized epithelial structure of the mammalian cochlea that produces endolymph, the potassium-rich fluid responsible for the positive endocochlear potential of the cochlear lumen. This positive extracellular potential is the major driving force for proper signal transduction by sensory cells in the ear, and thus normal hearing. The stria vascularis is the “battery” of the auditory organ. It is localized in the lateral wall of the cochlea, and consists of a multilayered highly vascularized epithelium. It is composed of three main cell types with distinct embryonic origins: the marginal cells derived from the otic epithelium, the intermediate cells which are specialized melanocyte-like cells derived from migratory neural crest cells, and the basal cells that are derived from otic mesenchyme. Mesoderm-derived blood vessels are interspersed between these cells throughout the stria. Defects in the development of the stria vascularis are part of a number of inheritable deafness syndromes in humans, including Hirschsprung disease and Waardenburg, Jervell and Lange-Nielsen, Bartter and SeSAME syndromes. Over the past decade, a great effort has been made to understand the development of the sensory cells in the mammalian cochlea with the aim of applying their developmental principles to regenerative therapies. By contrast, very little is known about the developmental potential of the stria vascularis, or even the mechanisms of strial degeneration due to aging. Our long-term goal is to understand the principles that govern the development of the stria and apply them to devise reparative and regenerative therapies for cases of congenital strial defects or strial presbycusis. Neural crest cells are a transient population of multipotent migratory embryonic cells. In the inner ear, neural crest cells give rise to the glia of the VIIIth ganglion and the intermediate cells of the stria vascularis. Intermediate cells are necessary for normal strial function and although they seem to share a common origin with melanoblasts, melanin itself is not necessary for hearing. Mutations that affect neural crest development or migration often result in syndromes that include deafness. Mutations of the human endothelin receptor B gene (Ednrb) result in Hirschsprung's disease. The sensorineural deafness in this syndrome is a consequence of the atrophied stria vascularis that lacks intermediate cells. The goal of this proposal is to investigate the migration, differentiation and interactions of neural crest-derived intermediate cells with other cells in the stria vascularis and the role that Endothelin signaling plays in these processes.