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Microtubule-mediated mechanisms underlying hair cell development and deafness

毛细胞发育和耳聋的微管介导机制

基本信息

批准号：
10571874
负责人：
Xiaowei Lu
金额：
$ 45.06万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571874
关键词：
Actins Alleles Apical Auditory Cell Culture Techniques Cells Cilia Cochlea Cochlear duct Cytoskeleton Data Defect Development Disease Ear Economic Burden Embryonic Development Ensure Environment Environmental Risk Factor Epithelium Equilibrium Foundations Functional Regeneration G-Protein Signaling Pathway GTP-Binding Proteins Genes Genetic Guanine Nucleotide Exchange Factors Hair Hair Cells Hearing Heterotrimeric GTP-Binding Proteins Human Image In Vitro Inherited Injury Kinocilium Knock-out Knockout Mice Knowledge Lateral Ligands Link Maintenance Mammals Medial Mediating Medical Membrane Microtubules Molecular Morphogenesis Morphology Motor Mutant Strains Mice Names Natural regeneration Organelles Pathway interactions Pattern Peripheral Phenotype Phosphatidylinositols Phosphotransferases Positioning Attribute Proteins Publishing Regulation Role Scaffolding Protein Sensorineural Hearing Loss Sensory Hair Shapes Signal Pathway Signal Transduction Signaling Protein Stereocilium Structure Testing Therapeutic Tissues Transducers WNT Signaling Pathway Work beta catenin cellular microvillus conditional knockout deafness disability gain of function genetic deafness hair cell regeneration hearing impairment in vivo insight loss of function mechanotransduction migration morphogens mutant neural novel permanent hearing loss planar cell polarity programs protease-activated receptor 3 protein activation rational design receptor recruit repaired sensor social sound stem cell technology

项目摘要

The actin-based stereociliary bundle (or hair bundle) on the apex of auditory hair cells serves the critical function of converting sound energy to electric signals. Defects in hair bundle development and maintenance due to genetic and environmental factors are a leading cause for sensorineural deafness. A long-term objective of this work is to gain a mechanistic understanding of hair bundle morphogenesis programs, including secreted morphogens and their downstream signaling effectors and cytoskeletal regulators. Formation of the V-shaped hair bundle is integrally linked to planar polarization of the hair cell apical cytoskeleton, which is initiated by the peripheral migration of the kinocilium, the hair cell primary cilium. Recent advances demonstrate that hair cell intrinsic planar polarity, which we name iPCP to be concise, is regulated by several planar polarized, cell- intrinsic signaling modules and microtubule motors. At the tissue-level, the non-canonical Wnt/Planar Cell Polarity (PCP) pathway aligns hair cell orientation along the medial-lateral (or neural-abneural) axis of the cochlear duct. While disrupted tissue-level PCP signaling causes hair bundle misoriention, defective iPCP signaling results in both misoriented and misshapen hair bundles with a mispositioned kinocilium. Despite its importance for hair bundle morphogenesis, how iPCP is regulated by developmental signals and how iPCP and PCP signaling are integrated remain poorly understood. To fill these knowledge gaps, this application leverages our recent exciting discoveries and aims to elucidate the mechanisms by which a novel Wnt/G protein signaling pathway coordinately controls iPCP and PCP during hair bundle morphogenesis. While Wnt/β-catenin and Wnt/PCP pathways have been extensively studied, little is known about the in vivo function and mechanisms of Wnt/G protein signaling. Our aims are built on a strong foundation of preliminary data, showing that Wnt ligands secreted by the cochlear epithelium activate heterotrimeric G protein and PI3K signaling to control both iPCP and PCP. We have identified genes required for G protein activation in the cochlea, providing clues to the molecular mechanism. We propose to use gain- and loss-of-function alleles in vivo, ex vivo cochlear explants and cell culture studies in vitro to define critical components of the Wnt/G protein pathway and its integration with the Wnt/PCP pathway. In Aim 1, we will delineate the signal transduction machinery of the Wnt/G protein pathway by determining the roles of specific Wnt ligand, Frizzled receptors and downstream signal transducers. In Aim 2, we investigate the role of the iPCP component Par3 in Wnt-induced G protein activation. In Aim 3, we will test whether Wnt/G protein signaling is regulated by multiple G protein GEFs during cochlear morphogenesis. Ultimately, insights into this new Wnt signaling pathway may facilitate devising rational therapies to stimulate hair bundle repair following injury and to regenerate auditory hair cells through stem cell technologies.

听觉毛细胞顶端的肌动蛋白基立体纤毛束（或毛束）起关键作用