Molecular mechanisms underlying morphogenesis of the tectorial membrane

盖膜形态发生的分子机制

• 批准号: 10210885
• 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/10210885
• 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.

项目摘要/摘要 Tecorial膜（TM）是位于Corti器官上的细胞外基质（ECM）。 TM播放 在声波的频率选择，传播和扩增中的重要作用。 TM的畸形 导致遗传性听力障碍。由于TM是细胞结构，因此其独特特性来自 矩阵架构。 TM表现出复杂的超微结构特征和特定领域的图案 矩阵组织。但是，组织特定矩阵结构的机制 在细胞外面是未知的。它是否取决于其分子组成和/或组织模式？我们 观察到需要通过糖基磷脂酰肌醇（GPI）锚固的A-Tectorin/Tecta进行表面螺旋。 为了防止分泌的TM分量扩散到Scala介质的腔空间中并形成TM 产生TM的细胞顶部表面上的基质。 TECTA的发布在生长中起着至关重要的作用 TM层。我们的体外测定表明，TECTA通过多个从生产细胞中释放 机制以及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。在此提案中，我们将确定tecta的分子机制 调解特定TM体系结构的组织。我们将表征发生的分子动力学 在矩阵成熟期间。我们的结果将提供第一个证据，表明复杂的ECM结构是如何的 在分子水平的细胞外空间中建立并成熟。这将为您提供新颖的见解 形态发生的过程以及遗传性和与年龄相关的听力缺陷的机制。