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Regulation of inner ear development by FGF signals and effectors

FGF 信号和效应器调节内耳发育

基本信息

批准号：
10552052
负责人：
Suzanne L Mansour
金额：
$ 41.41万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-05 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552052
关键词：
Ablation Address Affect Age Auditory Candidate Disease Gene Cell Differentiation process Cell Survival Cells Cochlea Cochlear implant procedure Data Defect Development Dominant-Negative Mutation Doxycycline Epithelium Equilibrium FGF10 gene FGF3 gene Fibroblast Growth Factor Fibroblast Growth Factor Receptors Future Ganglia Generations Genes Goals Health Care Costs Hearing In Vitro Individual Investigation Knockout Mice Knowledge Labyrinth Ligands Maintenance Mediating Mesenchymal Messenger RNA Molecular Morphogenesis Morphology Mus Neurons Otic Placodes Pattern Phenotype Proliferating Receptor Protein-Tyrosine Kinases Regulation Repression Role Sensory Signal Pathway Signal Repression Signal Transduction Signaling Molecule Specific qualifier value System Testing Tissues Transplantation cell type combinatorial conditional knockout conditional mutant extracellular fibroblast growth factor receptor 2b gene function genetic approach genome-wide analysis hearing impairment hearing restoration in vivo inner ear development light intensity loss of function malformation molecular marker mouse model mutant nerve supply neural neuroblast neurogenesis novel otoconia overexpression permanent hearing loss social spiral ganglion transcription factor

项目摘要

Morphogenesis of the inner ear epithelium requires coordinated deployment of several signaling pathways and disruptions cause abnormalities of hearing and/or balance. With the advent of cochlear implantation to treat hearing loss even in cases of inner ear malformation, it is critical to understand exactly how such malformations affect the auditory ganglia and innervation. Also, in light of the intense focus on in vitro generation of inner ear cell types for transplantation and in vivo manipulation of developmental signaling molecules to promote differentiation of various inner ear cells for hearing restoration, elucidating the roles and regulation of such signals and their effectors governing otic differentiation and morphogenesis are necessary to advance treatment. The genes encoding FGF3 and FGF10, ligands that signal through FGFR2b and FGFR1b, are expressed dynamically throughout otic development in both epithelial and ganglion domains. Studies conducted by the Mansour Lab of both conventional Fgf3 and Fgf10 conditional knockout mice and those expressing a doxycycline-inducible ligand trap (dnFGFR2b) that rapidly inhibits signaling through both FGFR1b and FGFR2b, showed that Fgf3 and Fgf10 are not required in the placode lineage for otocyst formation, but are required subsequently for otocyst patterning, neuroblast maintenance, epithelial proliferation and both vestibular and cochlear morphogenesis. Furthermore, the first genome wide analyses of otocyst mRNA revealed FGFR2b/1b signaling targets that define novel candidates for genes involved in otic morphogenesis and function. This proposal has two Aims addressing the hypotheses that 1) FGFR2b/1b signaling is required continuously for both otic neuroblast specification and maintenance, and that at later stages, mesenchymal signaling, as well as that in the epithelial and ganglion domains, is required for cochlear epithelial differentiation and ganglion maintenance and 2) FGFR2b/1b downstream target genes mediate some or all of the effects of FGFR2b/1b signaling on otic morphogenesis and gangliogenesis. To determine the early role of FGFR2b/1b signaling in otic ganglion formation and its later role in epithelial differentiation and ganglion maintenance, DOX-induced ubiquitous and CRE-limited expression of dnFGFR2b will be employed and morphology and molecular markers of otic patterning, proliferation and survival in both tissues will be assessed. To determine the roles of downstream targets of FGFR2b/1b signaling, two genes encoding transcription factors that are activated by FGFR2b/1b signaling and one gene encoding a BMP signaling regulator that is repressed by FGFR2b/1b signaling will be studied. Otic conditional mutants will be generated for each gene, and their morphologic and functional development will be assessed. In addition, the extent to which the BMP regulator contributes to the dnFGFR2b phenotypes and the effects of overexpressing the BMP regulator will be assessed. The results will contribute new knowledge that will facilitate future efforts to manipulate the FGF signaling system for hearing restoration.

内耳上皮的形态发生需要多种信号通路的协调部署