Molecular mechanisms underlying morphogenesis of the tectorial membrane

盖膜形态发生的分子机制

• 批准号: 10348212
• 负责人: Sung Jin Park
• 金额: $ 32.41万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-09 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348212
• 关键词: 3D Print; Apical; Architecture; Auditory; Biological Assay; C-terminal; Cell surface; Cells; Cochlear duct; Collagen; Collagen Fibril; Complex; Data; Development; Developmental Biology; Diffusion; Disease; Exhibits; Extracellular Matrix; Extracellular Space; Fiber; Frequencies; GPI Membrane Anchors; Glycosylphosphatidylinositols; Growth; In Vitro; Individual; Inherited; Location; Mediating; Modeling; Molecular; Morphogenesis; Organ of Corti; Pattern; Peptides; Physiological; Play; Presbycusis; Process; Property; Proteins; Radial; Reconstructive Surgical Procedures; Research; Role; Shapes; Stereotyping; Structure; Surface; Testing; Thinness; Time; Tissue Engineering; extracellular; hearing impairment; in vitro Assay; in vivo; insight; limbal; malformation; molecular dynamics; novel; polymerization; prevent; regenerative therapy; sound; tectorial membrane

PROJECT SUMMARY/ABSTRACT The tectorial membrane (TM) is an extracellular matrix (ECM) that lies over the organ of Corti. The TM plays important roles in frequency selection, propagation, and amplification of sound waves. Malformation of the TM causes hereditary hearing deficits. Since the TM is an acellular structure, its unique properties arise from the matrix architecture. The TM exhibits sophisticated ultrastructural features and domain-specific patterns of matrix organization. However, the mechanisms by which the specific matrix architectures are organized outside of cells are unknown. Is it determined by its molecular composition and/or mode of organization? We observed that surface-tethering of a-tectorin/TECTA via a glycosylphosphatidylinositol (GPI)-anchor is required to prevent diffusion of secreted TM components into the luminal space of the scala media and to form the TM matrix on the apical surface of TM-producing cells. The release of TECTA plays a critical role in the growth of the TM layers. Our in vitro assays show that TECTA is released from the producing cells by multiple mechanisms and that the different forms of TECTA released by these distinct mechanisms show unique multimerization activities. In this proposal, we will determine the molecular mechanism by which TECTA mediates the organization of specific TM architecture. We will characterize molecular dynamics that occur during the matrix maturation. Our results will provide the first evidence of how a complex ECM structure is established and matures in the extracellular space at the molecular level. This will provide novel insights into the process of morphogenesis as well as the mechanism of hereditary and age-related hearing deficits.

项目概要/摘要 盖膜 (TM) 是位于柯蒂氏器上方的细胞外基质 (ECM)。 TM玩的 在声波的频率选择、传播和放大中发挥着重要作用。 TM畸形 导致遗传性听力缺陷。由于 TM 是一种无细胞结构，其独特的性质源自 矩阵架构。 TM 表现出复杂的超微结构特征和特定领域的模式 矩阵组织。然而，特定矩阵架构的组织机制 细胞外未知。它是由其分子组成和/或组织模式决定的吗？我们 观察到需要通过糖基磷脂酰肌醇 (GPI) 锚定 a-tectorin/TECTA 的表面束缚 防止分泌的 TM 成分扩散到 scala 介质的管腔空间中并形成 TM TM 产生细胞顶端表面的基质。 TECTA的发布在成长中发挥着至关重要的作用 TM 层。我们的体外试验表明，TECTA 通过多种方式从生产细胞中释放出来。 机制，并且这些不同机制释放的不同形式的 TECTA 显示出独特的 多聚化活动。在本提案中，我们将确定 TECTA 的分子机制 协调特定 TM 架构的组织。我们将描述发生的分子动力学 在基质成熟过程中。我们的结果将提供第一个证据来证明复杂的 ECM 结构是如何的 在分子水平上在细胞外空间中建立并成熟。这将提供新的见解 形态发生的过程以及遗传性和年龄相关性听力缺陷的机制。