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.

项目总结/文摘